Methods and compositions for the treatment of hair loss

ABSTRACT

Compositions and methods for the treatment of hair growth and the prevention of hair loss.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to the benefit of U.S. ProvisionalPatent Application Ser. No. 62/883,809, filed on Aug. 7, 2019 and U.S.Provisional Patent Application Ser. No. 62/895,869, filed on Sep. 4,2019 and U.S. Provisional patent application Ser. No. 63/100,611, filedon Mar. 23, 2020, the disclosures of which are hereby incorporated byreference in their entireties.

1. FIELD OF THE INVENTION

The present invention is directed to the use of certain prostaglandinanalogues alone and in combination with other compounds such ascyclosporine, to prevent hair loss and/or grow hair. The presentinvention is also directed to formulations containing prostaglandinanalogues and cyclosporine to grow hair or prevent hair loss on thescalp and other areas of the body. The present invention is alsodirected to formulations and methods for treating certain hair lossdisorders such as androgenetic alopecia and alopecia areata.

2. BACKGROUND OF THE INVENTION

Hair loss is a psychologically devastating condition causing significantpsychological stress in both men and women. Thirty percent of all maleswill experience some hair loss by the age of thirty years, fifty percentby the age of fifty years, and eighty percent by the age of seventyyears. By age sixty, forty percent of women experience hair loss.Negative effects on quality of life due to hair loss have been reportedby men and in particular adolescents and women.

Hair growth is generally divided into four phases.

The anagen phase is the phase of active hair growth which lasts two tosix years but generally lasts three to five years with scalp hair.During anagen, the epithelial compartment of the hair follicle undergoesrapid proliferation, with the greatest proliferation in the bulb matrixcells and follicles assume bulb anagen morphology. In fact, it ispossible to determine which phase a hair is in by studying the folliclebulb morphology. The catagen phase is a short transitional phase betweenthe anagen phase and the telogen phases which lasts seven to fourteendays with scalp hair. The telogen phase is called the “resting phase”where hair growth ceases before the hair is eventually shed andgenerally lasts four to eight weeks and the dermal papilla fullyseparates from the hair follicle. A fourth stage, which is either theend of the telogen phase or the beginning of the anagen phase, is theexogen phase where the old hair is shed.

The anagen phase begins again with the dermal papilla moving back up tomeet the hair follicle and new hair growth begins again where the newhair ejects the old hair (see FIG. 2).

In humans without a hair loss disorder, about ninety percent of thehairs on the scalp are in the anagen phase, about one to two percent ofhairs are in the catagen phase and about eight to nine percent of scalphair are in the telogen phase. With the onset of androgenetic alopecia,a greater proportion of hair are in the telogen phase and fewer hairsfewer are in the anagen phase. The patient has significantly fewerfollicles than people suffering no hair loss disorder, with a typicalbald person having roughly three hundred hair follicles per square inchon their scalp while a person with no hair loss disorder will have aboutfour hundred and fifty hair follicles per square inch. Perhaps moreimportantly, in the active hair follicles in a person suffering fromandrogenetic alopecia, more of the hairs in the follicles will be vellushairs rather than terminal hairs which are longer, thicker in diameterand more pigmented. Further, an increased number of hairs will be in thetelogen phase.

3. SUMMARY OF THE INVENTION

The Summary of Invention includes the following embodiments:

-   -   1. A composition for use in the treatment of hair loss        comprising about 0.05%-0.1% w/w, w/v, or v/v latanoprost or        latanoprost acid and 0.05%-0.1% w/w, w/v, or v/v cyclosporine A        and 1.0%-15.0% w/w, w/v, or v/v diethylene glycol monoethyl        ether.    -   2. The composition of embodiment 1 wherein the composition has        about 0.05% w/w, w/v, or v/v latanoprost or latanoprost acid and        about 0.06% w/w, w/v, or v/v cyclosporine A and about 10% w/w,        w/v, or v/v diethylene glycol monoethyl ether.    -   3. The composition of embodiment 2 further comprising oleyl        alcohol.    -   4. The composition further comprising polyethylene glycol or        propylene glycol.    -   5. A composition for use in growing hair on a patient        experiencing hair loss comprising about 0.05%-0.1% w/w, w/v, or        v/v latanoprost or latanoprost acid and 0.05%-0.1% w/w, w/v, or        v/v cyclosporine A and 5.0%-15.0% w/w, w/v, or v/v CAPTEX 300        EP/NF.    -   6. The composition of embodiment 5 wherein composition comprises        0.06% w/w, w/v, or v/v latanoprost or latanoprost acid and 0.08%        w/w, w/v, or v/v cyclosporine A.    -   7. The composition of embodiment 6 further comprising 10% w/w,        w/v, or v/v CAPTEX 300 EP/NF.    -   8. A composition for use in treating hair loss comprising about        0.05%-0.1% w/w, w/v, or v/v travoprost or travoprost acid and        0.05%-0.1% w/w, w/v, or v/v cyclosporine A.    -   9. The composition according to embodiment 8 further comprising        one selected from the group consisting of diethylene glycol        monoethyl ether, CAPTEX 300 EP/NF, propylene glycol and        polyethylene glycol.    -   10. The composition according to embodiments 1, 5, 8 and 9        further comprising oleic acid.    -   11. A method of preventing hair loss on a patient comprising        administering a formulation according to one of embodiments 1,        5, 8 and 9 to a patient in need thereof.    -   12. The method of embodiment 11 wherein the patient is suffering        from alopecia areata and the formulation is applied once a day        to areas on the scalp experiencing hair loss.    -   13. The method of embodiment 12 wherein the formulation is        applied twice a day.    -   14. A method for causing hair growth in a patient suffering from        hair loss comprising administering a formulation according to        one of embodiments 1, 5, 8 and 9 to a patient in need thereof        and the method downregulates T cell infiltrates in the area of        the follicular bulb.    -   15. The method of embodiment 14 wherein the patient experiences        hair growth to a greater extent by applying the formulation of        one of embodiments 1, 5, 8 and 9 as compared to if the patient        had not applied the formulation.    -   16. The method of embodiments 10-15 wherein the formulation        maintains the hair in anagen phase longer than if the        formulation had not been applied.    -   17. The method of embodiment 14 wherein the patient reverses a        substantial amount of hair loss.    -   18. The method of embodiment 14 wherein the formulation        comprises 0.06% w/w, w/v, or v/v latanoprost acid and 0.08% w/w,        w/v, or v/v cyclosporine A and a pharmaceutically acceptable        solvent and a penetration enhancer.    -   19. The method of growing hair on a scalp of a patient wherein        the formulation comprises 0.1% w/w, w/v, or v/v latanoprost or        latanoprost free acid and cyclosporine.    -   20. The method of embodiment 19 wherein the cyclosporine is        cyclosporine A.    -   21. A composition for use in the treatment of hair loss        comprising about 0.05%-0.1% w/w, w/v, or v/v bimatoprost and        0.05%-0.1% cyclosporine A and 1.0%-25.0% w/w, w/v, or v/v        diethylene glycol monoethyl ether.    -   22. A composition for use in growing hair comprising about        0.05%-0.1% w/w, w/v, or v/v bimatoprost and 0.05%-0.1%        cyclosporine A and 1.0%-15.0% w/w, w/v, or v/v diethylene glycol        monoethyl ether.    -   23. A composition for use in the treatment of hair loss or to        grow hair comprising about 0.05%-0.5% w/w, w/v, or v/v        latanoprost or latanoprost acid and 1.0%-7.0% w/w, w/v, or v/v        minoxidil or minoxidil sulphate.    -   24. The composition of embodiment 23 wherein the composition has        about 0.1% or 0.3% w/w, w/v or v/v latanoprost or latanoprost        acid and about 5.0% w/w minoxidil or minoxidil sulphate.    -   25. The composition of embodiment 23 further comprising one        selected from the group consisting of oleyl alcohol, ethanol,        oleic acid and diethylene glycol monoethyl ether.    -   26. The composition of embodiment 23 wherein the composition has        one selected from the group consisting of 0.1%, 0.2% or 0.3%        w/w, w/v, or v/v latanoprost or latanoprost acid and one        selected from the group consisting of 4.0%, 5.0%, 6.0% and 7.0%        w/w, w/v, or v/v minoxidil or minoxidil sulphate.    -   27. A composition for use in the treatment of hair loss or to        grow hair comprising about 0.05%-0.1% w/w, w/v, or v/v        bimatoprost or bimatoprost acid and 1.0%-5.0% w/w, w/v, or v/v        minoxidil or minoxidil sulphate.    -   28. The composition of embodiment 27 wherein the composition has        one selected from the one selected form the group consisting of        0.1%, 0.2% and 0.3% w/w, w/v, or v/v bimatoprost and one        selected from the group consisting of 4.0%, 5.0%, 6.0% and 7.0%        w/w, w/v, or v/v minoxidil.    -   29. The composition of embodiment 27 further comprising oleyl        alcohol, oleic acid or ethanol.    -   30. The composition of embodiment 27 further comprising        propylene glycol or polyethylene glycol.    -   31. A composition for use in the treatment of hair loss or to        grow hair comprising about 0.05%-0.5% w/w, w/v, or v/v        travoprost or travoprost free acid and 1.0%-7.0% w/w, w/v, or        v/v minoxidil or minoxidil sulphate.    -   32. The composition of embodiment 31 wherein the composition has        about 0.1% w/w, w/v, or v/v travoprost or travoprost free acid        and about 5.0% w/w, w/v, or v/v minoxidil or minoxidil sulphate        and at least 5% w/w, w/v, or v/v diethylene glycol monoethyl        ether.    -   33. The composition of any of the embodiments 1-10 and 20-32        wherein the composition is applied to the skin beneath the        eyebrows of a patient to cause eyebrows to grow.    -   34. The composition of any of the embodiments 1-10 and 20-32        wherein the composition is applied to the upper or lower eyelid        margin of a patient to cause eyelashes to grow.    -   35. The composition of any of the embodiments 1-32 wherein the        composition is applied to the skin beneath the mustache or beard        of a patient to cause hairs of the mustache or beard to grow.    -   36. A method of converting vellus hair to terminal hair by        application of the formulation of embodiments 1-10 and 21-32 to        the locale of the vellus hair on a patient.    -   37. A method of converting intermediate hair to terminal hair by        application of the formulation of embodiment 23 to the locale of        the vellus hair on a patient.    -   38. A method of increasing at least one selected from length,        thickness and pigmentation of hair by the application of a        composition of embodiment 1-10 or 21-32 to the scalp of a        patient.    -   39. The composition of embodiment 23, 27, 31 or 33 wherein the        composition is a gel.    -   40. The composition of embodiment 39 wherein the gel is applied        to the eyebrows in one selected from the group consisting of        once a day, twice a day or three times a day.    -   41. The composition of embodiment 39 wherein the gel comprises        at least one selected from the group consisting of sodium        carboxymethyl cellulose, hyaluronic acid or carbodiimide and or        mixtures thereof.    -   42. The composition of embodiment 41 wherein the sodium        carboxymethyl cellulose is selected form the group consisting of        low viscosity (90,000 Daltons), medium viscosity (250,000        Daltons) and high viscosity (700,000 Daltons) carboxymethyl        cellulose and/or mixtures thereof.    -   43. The composition of embodiments 40 and 41 wherein the gel is        applied to the eyebrows once or twice a day.    -   44. A first composition comprising latanoprost or latanoprost        acid and minoxidil or minoxidil sulphate wherein the application        of the composition to the skin results in a faster onset of hair        growth as compared to either latanoprost or latanoprost acid and        minoxidil or minoxidil sulphate applied as monotherapy to the        skin and at the same concentration as in the first composition.    -   45. The composition of embodiment 44 wherein the first        composition comprising latanoprost or latanoprost acid and        minoxidil are present at the same individual concentrations as        latanoprost or latanoprost acid and minoxidil applied alone as        monotherapies.    -   46. The composition of embodiments 44 or 45 wherein the        composition is applied to one selected from the group consisting        of the scalp, the skin beneath the eyebrows, upper eyelid        margin, lower eyelid margin and the face.    -   47. A first composition comprising latanoprost or latanoprost        acid and minoxidil or minoxidil sulphate wherein the application        of the first composition to the skin results in greater hair        growth as compared to either latanoprost or latanoprost acid and        minoxidil or minoxidil sulphate applied to the skin alone as        monotherapies at the same individual concentrations as they        exist in the first composition.    -   48. The first composition of embodiment 47 wherein the first        composition comprising latanoprost or latanoprost acid and        minoxidil or minoxidil sulphate when applied to the scalp, the        skin beneath the eyebrows, upper eyelid margin, lower eyelid        margin and the face results in hair growth resulting in one        selected from the group consisting of longer hair than either        latanoprost or latanoprost acid and minoxidil applied alone as        monotherapies at the same concentration as they exist in the        first composition.    -   49. The first composition of embodiment 47 comprising        latanoprost or latanoprost acid and minoxidil or minoxidil        sulphate when applied to the skin results in greater individual        hair diameter or circumference than either latanoprost or        latanoprost acid and minoxidil applied alone to the skin at the        same concentration as monotherapies.    -   50. The first composition of embodiment 47 comprising        latanoprost or latanoprost acid and minoxidil or minoxidil        sulphate when applied to the skin results in greater melanin        concentration of individual hairs as compared to applying        latanoprost or latanoprost acid and minoxidil or minoxidil        sulphate applied alone to the skin at the same concentration as        monotherapies.    -   51. A first composition comprising travoprost or travoprost free        acid and minoxidil or minoxidil sulphate when applied to the        skin results in hair growth resulting in longer hair than either        travoprost or travoprost acid and minoxidil or minoxidil        sulphate applied alone wherein the concentration of travoprost        or travoprost acid and minoxidil or minoxidil sulphate are at        the same concentrations as compared to travoprost or travoprost        acid and minoxidil or minoxidil sulphate monotherapies.    -   52. The first composition of embodiment 51 comprising travoprost        or travoprost free acid and minoxidil or minoxidil sulphate        wherein the application of the first composition to the skin        results in greater hair growth as compared to either travoprost        or travoprost acid and minoxidil or minoxidil sulphate applied        to the skin alone as monotherapies at the same individual        concentration as they exist in the first composition.    -   53. The first composition of embodiment 51 comprising travoprost        or travoprost free acid and minoxidil or minoxidil sulphate when        applied to the skin results in greater individual hair diameter        or circumference as compared to either travoprost or travoprost        free acid and minoxidil or minoxidil sulphate applied alone to        the skin as monotherapies at the same individual concentration        as they exist in the first composition.    -   54. The first composition of embodiment 47 comprising travoprost        or travoprost free acid and minoxidil or minoxidil sulphate when        applied to the skin results in greater melanin concentration of        individual hairs as compared to applying travoprost or        travoprost free acid and minoxidil or minoxidil sulphate applied        alone to the skin at the same concentration as monotherapies.    -   55. A method of stimulating hair growth on the scalp by applying        to the scalp a composition selected from the group consisting of        one of the embodiments 1-10 or 21-32 or 39-54.    -   56. A method of stimulating hair growth on the scalp by applying        to the scalp a composition selected from the group consisting of        one of Formulations I-XXXXX.    -   57. A method for stimulating hair follicles to increase hair        growth and one or more properties selected from the group        consisting of individual hair length, individual hair diameter        or circumference, individual hair darkness, melanin content of        each individual hair, an increase of the ratio of terminal hair        to velus hair per square inch of skin, and an increase of dark        hair to grey hair in the area of application comprising the        application to mammalian skin at the locale of hair follicles of        an effective amount of a composition comprising one selected        from the group consisting of one of the embodiments 1-10 or        21-32, 39, 41 or 42 or Formulations I-XXXXX.    -   58. A method for stimulating hair follicles to increase hair        growth and one or more properties selected from the group        consisting of individual hair length, individual hair diameter        or circumference, individual hair darkness, melanin content of        each individual hair, increase the ratio of terminal hair to        velus hair per square inch of skin, and an increase of dark hair        to grey hair in the area of application comprising the        application to mammalian skin at the locale of the follicles of        an effective amount of a composition comprising one selected        from the group consisting of one of the Formulations I-XXXXX.    -   59. The method of embodiments 57 and 58 wherein the composition        is applied to one selected from the group consisting of the        scalp, the epidermis layer beneath the eyebrows, lower eyelid        margin, upper eyelid margin and the face.    -   60. A method for increasing the number of terminal hairs on the        skin by applying an effective amount on the skin or epidermis of        a composition comprising one selected from the group consisting        of one of the embodiments 1-10 or 21-32 or 39, 41 or 42 or        Formulations I-XXXXX.    -   61. A method for increasing the number of terminal hairs on the        scalp by applying an effective amount to mammalian skin of a        composition comprising one selected from the group consisting of        one of the of one of the embodiments 1-10 or 21-32 or 39, 41, 42        and 54 or Formulations I-XXXXX.    -   62. A method of converting gray hair to darker hair by applying        an effective amount to mammalian skin of a composition        comprising one selected from the group consisting of one of the        embodiments 1-10 or 21-32 or 39, 41, 42 and 54 or Formulations        I-XXXXX.    -   63. A method of converting gray hair to darker hair or        increasing the melanin content in hair by applying an effective        amount to mammalian skin in proximity to the hair follicles of a        composition comprising one selected from the group consisting of        embodiments 1-10 or 21-32 or 39-54 or one of the of one of the        Formulations I-XXXXX.    -   64. A method of increasing the melanin content of individual        hairs by applying an effective amount to mammalian skin in        proximity to the hair follicles of a composition comprising one        selected from the group consisting of one of the embodiments        1-10 or 21-32 or 39-54 or one of the Formulations I-XXXXX.    -   65. A method of darkening individual hairs by applying an        effective amount to mammalian skin in the area of skin with grey        hair of a composition comprising one selected from the group        consisting of one of the embodiments 1-10 or 21-32 or 39-54 or        one of Formulations I-XXXXX.    -   66. The method of embodiments 64 and 65 wherein the method        increases the melanin content and the keratin content of        individual hairs.    -   67. A method of increasing the diameter or circumference of        individual hairs by applying an effective amount to mammalian        skin in proximity to the hair follicle of a composition        comprising one selected from the group consisting of one of the        embodiments 1-10 or 21-32 or 39-54 or one of Formulations        I-XXXXX.    -   68. A method of increasing the diameter, circumference or length        of individual hairs by applying an effective amount to hair        follicles of a composition comprising one selected from the        group consisting of one of the of the embodiments 1-10 or 21-32        or 39-54 or one of Formulations I-XXXXX.    -   69. The method of embodiments 60-68 wherein the composition is        applied to one selected from the group consisting of the scalp,        the skin beneath the eyebrows, upper eyelid margin, lower eyelid        margin and the face.    -   70. The method of embodiment 69 wherein the mammal is a human.    -   71. A method of preventing hair loss in a patient undergoing        chemotherapy comprising administering a formulation selected        from the group consisting of formulation I-XXXXX or embodiments        1-10 or 21-32 or 39-54 and applying the embodiment or        formulation to one selected from the group consisting of the        scalp, the epidermis layer beneath the eyebrows, the upper        eyelid margin and lower eyelid margin or the face before, during        or after chemotherapy.    -   72. The method of embodiment 71 when the formulation is applied        before the patient undergoes chemotherapeutic treatment to        reduce the amount of hair loss.    -   73. The method of embodiment 72 wherein the formulation is        applied one selected from the group consisting of 45 days prior        to chemotherapeutic treatment, 30 days prior to chemotherapeutic        treatment, 25 days prior to chemotherapeutic treatment, 20 days        prior to chemotherapeutic treatment, 15 days prior to        chemotherapeutic treatment, 10 days prior to chemotherapeutic        treatment and either 9, 8, 7, 6, 5, 4, 3, 2 and 1 day prior to        chemotherapeutic treatment.    -   74. The method of embodiments 72 or 73 wherein the formulation        is applied from one selected from the group consisting of three        times a day, two times a day and once a day.    -   75. The method of embodiments 71-74 wherein the patient loses        less hair from at least one selected from the group consisting        of the scalp, eyebrows, eyelashes and face as compared to the        patient receiving no formulation for the same period of time.    -   76. The method of embodiment 75 wherein the hair from the at        least one selected from the group consisting of the scalp,        eyebrows, eyelashes and face is longer, darker and thicker as        compared to the patient receiving no formulation.    -   77. The method of embodiment 75 wherein the hair from the at        least one selected from the group consisting of the scalp,        eyebrows, eyelashes and face is more numerous as compared to the        patient receiving no formulation.    -   78. The method of embodiment 71 wherein the formulation is        applied while the patient is receiving chemotherapeutic        treatment.    -   79. The method of embodiment 78 wherein the formulation is        applied from one selected from the group consisting of three        times a day, two times a day and once a day to at least one        selected from the group consisting of scalp, eyebrows, eyelashes        and face.    -   80. The method of embodiment 79 wherein the patient loses less        hair selected from the group consisting of scalp, eyebrows,        eyelashes and face as compared to the patient applying no        formulation.    -   81. The method of embodiments 78 and 79 wherein the hair from        the at least one selected from the group consisting of the        scalp, eyebrows, eyelashes and face is longer, darker, more        numerous and thicker as compared to the patient receiving no        treatment.    -   82. The method of embodiments 78-81 wherein the patient applies        the formulation while receiving chemotherapeutic treatment.    -   83. The method of paragraph 82 wherein the patient applies the        formulation after the chemotherapeutic treatment is completed.    -   84. The method of embodiment 83 wherein the patient applies        formulation from one selected from the group consisting of one        month, two months, three months, four months, five months, six        months, seven months, eight months, nine months, ten months,        eleven months, twelve months, thirteen months, fourteen months,        fifteen months, sixteen months, seventeen months, eighteen        months, nineteen months, twenty months, twenty-one months,        twenty-two months, twenty-three months and twenty-four months        after completion of chemotherapeutic treatment.    -   85. The method of embodiment 84 wherein the hair from the at        least one selected from the group consisting of the scalp,        eyebrows, eyelashes and face is longer, darker, more numerous        and thicker as compared to the patient receiving no treatment        after chemotherapeutic treatment.    -   86. The method of embodiment 84 wherein application of the        formulations I-XXXXX or embodiments 1-10 or 21-31 or 39-54 to        one selected form the group consisting of the scalp, eyebrows,        eyelashes and face results in hair entering the anagen phase        sooner and/or for a longer duration than if the patient applied        no formulation.    -   87. The method of embodiment 85 wherein application of the        formulation to one selected form the group consisting of the        scalp, eyebrows, eyelashes and face results in hair entering the        anagen phase longer than if the patient applied no formulation.    -   88. Use of latanoprost or latanoprost acid and minoxidil or        minoxidil sulphate in combination for the treatment of hair loss        in a patient suffering therefrom.    -   89. The use of embodiment 88 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.08-0.5% w/v, w/w        or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 2%-8% w/v, w/w or w/v.    -   90. The use of embodiment 89 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.1-0.3% w/v, w/w or        v/v and minoxidil or minoxidil sulphate is present in a        concentration of one selected from the group consisting of 1%,        2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% and 10% w/v, w/w or v/v.    -   91. The use of embodiment 90 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.2% w/v, w/w or w/v        and minoxidil or minoxidil sulphate is present in a        concentration of about 5% w/v, w/w or v/v.    -   92. The use of embodiment 90 wherein latanoprost or latanoprost        is present in a concentration of about 0.3% w/v and minoxidil or        minoxidil sulphate is present in a concentration of about 5%        w/v, w/w or v/v.    -   93. The use of embodiment 90 wherein latanoprost is present in a        concentration of about 0.8% w/v and minoxidil is present in a        concentration of about 4% w/v.    -   94. The use of embodiments 88-93 wherein the hair loss is at        least one selected from the group consisting of scalp hair,        eyebrows, eyelashes or facial hair.    -   95. Use of latanoprost or latanoprost acid and minoxidil or        minoxidil sulphate in combination for growing hair in a patient.    -   96. The use of embodiment 95 wherein the patient is suffering        from hair loss.    -   97. The use of embodiment 95 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.08-0.5% w/v, w/w        or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 2%-8% w/v, w/w or v/v.    -   98. The use of embodiment 95 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.1-0.3% w/v, w/w or        v/v and minoxidil or minoxidil sulphate is present in a        concentration of 4%-7% w/v, w/w or v/v.    -   99. The use of embodiment 95 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.2% w/v, w/w or v/v        and minoxidil or minoxidil sulphate is present in a        concentration of about 4% w/v, w/w or v/v.    -   100. The use of embodiment 95 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.3% w/v, w/w or v/v        and minoxidil or minoxidil sulphate is present in a        concentration of about 5% w/v, w/w or v/v.    -   101. The use of embodiment 95 wherein latanoprost or latanoprost        acid is present in a concentration of about 0.1% w/v and        minoxidil or minoxidil sulphate is present in a concentration of        about 5% w/v, w/w or v/v.    -   102. The use of embodiments 88-93 and 97-100 wherein the hair        loss is at least one selected from the group consisting of scalp        hair, eyebrows, eyelashes or facial hair.    -   103. Use of travoprost or travoprost free acid and minoxidil or        minoxidil sulphate in combination for the treatment of hair loss        in a patient suffering therefrom.    -   104. The use of embodiment 103 wherein travoprost or travoprost        free acid is present in a concentration of about 0.08-0.5% w/v,        w/w or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 2%-8% w/v, w/w or v/v.    -   105. The use of embodiment 103 wherein travoprost or travoprost        free acid is present in a concentration of about 0.07%-0.3% w/v,        w/w or v/v and minoxidil or minoxidil sulphate is present in a        concentration of 4%-7% w/v, w/w or v/v.    -   106. The use of embodiment 103 wherein travoprost or travoprost        free acid is present in a concentration of about 0.2% w/v, w/w        or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 5% w/v, w/w or v/v.    -   107. The use of embodiment 103 wherein travoprost or travoprost        free acid is present in a concentration of about 0.3% w/v, w/w        or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 5% w/v, w/w or v/v.    -   108. The use of embodiment 103 wherein travoprost or travoprost        free acid is present in a concentration of about 0.1% w/v, w/w        or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 5% w/v, w/w or v/v.    -   109. The use of embodiments 103-108 wherein the hair loss is at        least one selected from the group consisting of scalp hair,        eyebrows, eyelashes or facial hair.    -   110. Use of travoprost or travoprost free acid and minoxidil or        minoxidil sulphate in combination for growing hair in a patient.    -   111. The use of embodiment 110 wherein the patient is suffering        from hair loss.    -   112. The use of embodiment 111 wherein travoprost or travoprost        free acid is present in a concentration of about 0.08-0.5% w/v,        w/w or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 2%-8% w/v, w/w or v/v.    -   113. The use of embodiment 111 wherein travoprost or travoprost        free acid is present in a concentration of about 0.1-0.3% w/v,        w/w or v/v and minoxidil or minoxidil sulphate is present in a        concentration of 4%-7% w/v, w/v, w/w or v/v.    -   114. The use of embodiment 95 wherein travoprost or travoprost        free acid is present in a concentration of about 0.2% w/v, w/w,        or v/v and minoxidil or minoxidil sulphate is present in a        concentration of about 5% w/v, w/w or v/v.    -   115. The use of embodiment 95 wherein travoprost or travoprost        is present in a concentration of about 0.3% w/v, w/w, or v/v and        minoxidil is present in a concentration of about 5% w/v, w/w, or        v/v.    -   116. The use of embodiment 95 wherein travoprost or travoprost        free acid is present in a concentration of about 0.07% or 0.08%        w/v, w/w, or v/v and minoxidil or minoxidil sulphate is present        in a concentration of about 4%, 5% or 6% w/v, w/w, or v/v.    -   117. The use of embodiments 103-108 wherein the hair loss is at        least one selected from the group consisting of scalp hair,        eyebrows, eyelashes or facial hair.    -   118. Use of bimatoprost and minoxidil or minoxidil sulphate in        combination for the treatment of hair loss in a patient        suffering therefrom.    -   119. The use of embodiment 118 wherein bimatoprost is present in        a concentration of about 0.08-0.5% w/v, w/w, or v/v and        minoxidil or minoxidil sulphate is present in a concentration of        about 2%-8% w/v, w/w, or v/v.    -   120. The use of embodiment 119 wherein bimatoprost is present in        a concentration of about 0.1-0.3% w/v, w/w, or v/v and minoxidil        or minoxidil sulphate is present in a concentration of 4%-7%        w/v, w/w or v/v.    -   121. The use of embodiment 118 wherein bimatoprost is present in        a concentration of about 0.2% w/v, w/v, w/w, or v/v and        minoxidil or minoxidil sulphate is present in a concentration of        about 5% w/v, w/w or v/v.    -   122. The use of embodiment 90 wherein bimatoprost is present in        a concentration of about 0.3% w/v, w/w or v/v and minoxidil or        minoxidil sulphate is present in a concentration of about 5%        w/v, w/w or v/v.    -   123. The use of embodiment 90 wherein bimatoprost is present in        a concentration of about 0.1% w/v, w/w or v/v and minoxidil or        minoxidil sulphate is present in a concentration of about 5%        w/v, w/w or v/v.    -   124. The use of embodiments 119-123 wherein the hair loss is at        least one selected from the group consisting of scalp hair,        eyebrows, eyelashes or facial hair.    -   125. Use of bimatoprost and minoxidil in combination for growing        hair in a patient.    -   126. The use of embodiment 95 wherein the patient is suffering        from hair loss.    -   127. The use of embodiment 119 wherein bimatoprost is present in        a concentration of about 0.08-0.5% w/v, w/w or v/v and minoxidil        is present in a concentration of about 2%-8% w/v, w/w or v/v.    -   128. The use of embodiment 127 wherein bimatoprost is present in        a concentration of about 0.08% w/v, w/w or v/v and minoxidil or        minoxidil sulphate is present in a concentration of 4%-7% w/v,        w/w or v/v.    -   129. The use of embodiment 95 wherein bimatoprost is present in        a concentration of about 0.9% w/, w/w or v/v and minoxidil or        minoxidil sulphate is present in a concentration of about 4%        w/v, w/w or v/v.    -   130. The use of embodiment 127 wherein bimatoprost is present in        a concentration of about 0.3% w/v, w/w or v/v and minoxidil or        minoxidil sulphate is present in a concentration of about 5%        w/v, w/w or v/v.    -   131. The use of embodiment 127 wherein bimatoprost is present in        a concentration of about 0.1% w/v and minoxidil or minoxidil        sulphate is present in a concentration of about 4% w/v, w/w or        v/v.    -   132. The use of embodiments 126-131 wherein the hair loss is at        least one selected from the group consisting of scalp hair,        eyebrows, eyelashes or facial hair.    -   133. A composition for use in the treatment of hair loss        comprising about 0.05%-0.5% w/v, w/w or v/v of one selected from        the group consisting of latanoprost and latanoprost acid and        1%-8% w/v, w/w or v/v minoxidil.    -   134. The composition of embodiment 133 wherein the composition        has about 0.3% w/v, w/w or v/v latanoprost or latanoprost acid        and about 5% w/v, w/w or v/v minoxidil or minoxidil sulphate.    -   135. The composition of embodiment 133 wherein the composition        has about 0.07% w/v, w/w or v/v latanoprost or latanoprost acid        and about 4-6% w/v, w/w or v/v minoxidil or minoxidil sulphate.    -   136. The composition of embodiment 133 further comprising oleyl        alcohol or ethanol.    -   137. The composition of embodiment 136 further comprising        propylene glycol.    -   138. The composition of embodiment 133 wherein the hair loss is        due to androgenetic alopecia.    -   139. The composition of embodiment 137 wherein the hair loss is        due to alopecia areata.    -   140. The composition of embodiment 137 further comprising acetic        acid one selected from the group consisting of polysorbate 60        and polyoxyethylene lauryl alcohol.    -   141. The composition of embodiment 134 further comprising acetic        acid one selected from the group consisting of polysorbate 60        and polyoxyethylene lauryl alcohol.    -   142. The composition of embodiment 137 further comprising        ethanol and at least one selected form the group consisting of        propylene glycol and polysorbate 80.    -   143. The composition of embodiment 142 wherein ethanol is        present in a concentration of about 25%-50% w/v.    -   144. The composition of embodiment 143 wherein the composition        further comprises oleyl alcohol.    -   145. The composition of embodiment 144 further comprising        diethylene glycol monoethyl ether.    -   146. The composition of embodiment 134 further comprising        ethanol, propylene glycol, water and at least one selected from        the group consisting of benzyl alcohol, oleic acid, oleyl        alcohol and polyoxyethylene lauryl alcohol.    -   147. The composition of embodiment 135 wherein the composition        comprises ethanol, propylene glycol, polysorbate, water and at        least one selected from the group consisting of acetic acid,        oleic acid and oleyl alcohol.    -   148. The composition of embodiment 147 wherein the composition        comprises acetic acid from about 0.1-0.5% w/v, w/w or v/v.    -   149. The composition of embodiment 147 wherein the composition        comprises propylene glycol from about 5%-60% w/v, w/w or v/v.    -   150. The composition of embodiment 133 wherein the composition        comprises ethanol, propylene glycol, polysorbate, water and at        least one selected from the group consisting of acetic acid,        oleic acid and oleyl alcohol.    -   151. A method of growing hair on the scalp by applying the        formulation of embodiment 134 to the scalp at least once a day        wherein the area of the scalp where the formulation is applied        will grow hair to a greater extent than an area of the scalp        receiving no formulation.    -   152. A method of growing hair comprising administering the        formulation of embodiment 135 to the skin wherein the        formulation causes hair in the telogen phase area of application        to the scalp to enter the anagen phase sooner than areas of the        scalp not receiving formulation.    -   153. A method of enhancing nail growth or treating brittle nail        syndrome in a patient suffering therefrom comprising        administering to the patient a formulation selected from        embodiments 1-10 or 21-31 or 35-54 and Formulations I-XXXXX        topically applied to the fingernails or cuticles of a patient at        least once a day.    -   154. The method of embodiment 153 wherein the method is useful        for treating a disorder of the toenail or fingernail selected        from the group consisting of nail psoriasis, psoriatic nail        dystrophy, brittle nail syndrome, increasing nail length and        thickness, onychia, onychiagryposis, onychia trophia,        onychocryptosis, onychodystrophy, onychogryposis, onycholysis,        onychomadesis, onychauxis, onychomycosis, onychorrhexis, tinea        unguium, onychophosis, onychoptosis, paronychia, pseudomonas,        pterygium and pterygium inversum unguis, koilonychia, subungual        hematoma or other trauma to the nail, folic acid deficiency,        leukonychia, nail patella syndrome, melanonychia, protein        deficiency, brittle and peeling nails, methyl methacrylate        damaged nails, vitamin C deficiency, vitamin deficiency, tinea        unguis, thinning nails associated with lichen planus, Raynaud's        disease, bleeding associated with rheumatoid arthritis, beau's        lines, and Mee's lines associated with certain kinds of        poisoning.    -   155. A method of stimulating melanogenesis in melanocytes in        cells in and around or in close proximity to the hair follicle        while simultaneously causing hair growth by administering one of        embodiments 1-10 or 21-31 or 35-54 or one of Formulations        I-XXXXX to hair follicles wherein the melanocytes will enter        into melanogenesis at a faster onset as compared to none of the        embodiments or Formulations being applied to the hair follicle.    -   156. The method embodiment 155 wherein the melanosomes in the        melanocytes produce more melanin as compared to none of the        embodiments or Formulations being topically applied to the hair        follicles.    -   157. The method of embodiment 155 wherein the melanosomes in the        melanocytes produce more of one selected from the group        consisting of black eumelanin, brown eumelanin, yellow        pheomelanin and red-brown pheomelanin as compared to none of the        embodiments or Formulations being applied to the hair follicles.    -   158. A method of hair growth wherein applying one selected from        the group of embodiments 5, 6, 7, 18, 19, 20, 23, 24-26, 44, 45,        47, 48, 49, 50, 88-93, 95, 97-101 results in new hair growth        which is darker as compared to no formulation being applied.    -   159. The method of embodiment 158 wherein applying one selected        from the group of embodiments 5, 6, 7, 18, 19, 20, 23, 24-26,        44, 45, 47, 48, 49, 50, 88-93, 95, 97-101 results in new hair        growth which is darker as compared to the same compositions in        embodiments 5, 6, 7, 18, 19, 20, 23, 24-26, 44, 45, 47, 48, 49,        50, 88-93, 95, 97-101 but wherein bimatoprost is exchanged for        latanoprost in the individual embodiments and at the same        concentration.    -   160. The method of embodiment 158 wherein applying one selected        from the group of embodiments 5, 6, 7, 18, 19, 20, 23, 24-26,        44, 45, 47, 48, 49, 50, 88-93, 95, 97-101 results in new hair        growth which is darker as compared to the same compositions in        embodiments 5, 6, 7, 18, 19, 20, 23, 24-26, 44, 45, 47, 48, 49,        50, 88-93, 95, 97-101 but wherein travoprost is exchanged for        latanoprost in the individual embodiments and at the same        concentration to the hair follicle.    -   161. A method of stimulating keratogenesis in keratinocytes in        cells in and around or in close proximity to the hair follicle        while simultaneously causing hair growth by administering one of        embodiments 1-10 or 21-31 or 35-54 or one of Formulations        I-XXXXX to hair follicles wherein the keratinocytes will enter        into keratogenesis at a faster onset and/or a longer duration as        compared to none of the embodiments or Formulations being        applied.    -   162. The method embodiment 161 wherein the keratinocytes produce        hair which is thicker or larger in diameter and/or circumference        as compared to none of the embodiments or Formulations being        topically applied to the hair follicles.    -   163. A method of hair growth wherein applying one selected from        the group of embodiments 5, 6, 7, 18, 19, 20, 23, 24-26, 44, 45,        47, 48, 49, 50, 88-93, 95, 97-101 results in new hair growth        which is one selected from the group consisting of thicker,        longer, greater in diameter and greater in circumference as        compared to no formulation being applied.    -   164. The method of embodiment 163 wherein applying one selected        from the group of embodiments 5, 6, 7, 18, 19, 20, 23, 24-26,        44, 45, 47, 48, 49, 50, 88-93, 95, 97-101 results in new hair        growth which is one selected from the group consisting of        thicker, longer, greater in diameter and greater in        circumference as compared to the same compositions in        embodiments 5, 6, 7, 18, 19, 20, 23, 24-26, 44, 45, 47, 48, 49,        50, 88-93, 95, 97-101 but wherein bimatoprost is exchanged for        latanoprost in the individual embodiments and at the same        concentration.    -   165. The method of embodiment 163 wherein applying one selected        from the group of embodiments 5, 6, 7, 18, 19, 20, 23, 24-26,        44, 45, 47, 48, 49, 50, 88-93, 95, 97-101 results in new hair        growth which is one selected from the group consisting of        thicker, longer, greater in diameter and greater in        circumference as compared to the same compositions in        embodiments 5, 6, 7, 18, 19, 20, 23, 24-26, 44, 45, 47, 48, 49,        50, 88-93, 95, 97-101 but wherein travoprost is exchanged for        latanoprost in the individual embodiments and at the same        concentration.    -   166. A method of increasing hair growth by applying one of        embodiments 1-10 or 21-31 or 35-54 or one of Formulations        I-XXXXX to hair follicles and applying infrared radiation to the        hair follicles.    -   167. The method of embodiment 166 wherein the infrared radiation        is applied after embodiments 1-10 or 21-31 or 35-54 or one of        Formulations I-XXXXX is applied to the hair follicles.    -   168. The method of embodiment 167 wherein the infrared radiation        is applied from above the hair follicle by a device for a period        of one selected from the group consisting of 1, 2, 3, 4, 5, 6,        7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23        and 24 hours.    -   169. A composition comprising tafluprost and minoxidil.    -   170. A composition for use in the treatment of hair loss        comprising about 0.05%-0.3% w/w, w/v, or v/v tafluprost and        1%-5% w/w, w/v, or v/v minoxidil.    -   171. The composition of embodiments 169 and 170, the composition        further comprising polyethylene glycol or propylene glycol and        ethanol.    -   172. The composition of embodiments 169, 170 and 171 further        comprising 0.1% w/v tafluprost and 5% w/v minoxidil.    -   173. A composition for use in treating hair loss comprising        tafluprost and finasteride.    -   174. The composition of embodiment 173 comprising 0.05% w/v-0.3%        w/v tafluprost and 0.05% w/v-0.3% w/v finasteride.    -   175. A composition for use in treating hair loss comprising        tafluprost and cyclosporine.    -   176. The composition of embodiment of claim 175 comprising        0.05%-0.1% w/w, w/v, or v/v tafluprost and 0.05%-0.1% w/w, w/v,        or v/v cyclosporine.    -   177. The composition of embodiment 176 wherein the cyclosporine        is cyclosporine A.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a description of the anatomy of a hair follicle including thesurrounding tissue;

FIG. 2 is a description of the various phases of hair growth;

FIG. 3 is the proposed mechanism of action of one of the formulations ofthe invention;

FIG. 4 shows hair growth on a 46 year old female patient applyingFormulation XX followed by Formulation XVIII; and,

FIG. 5 shows hair growth on a 53 year old male patient applyingFormulation XX followed by Formulation XVIII.

5. DETAILED DESCRIPTION OF THE INVENTION

A. Prostaglandin Analog

Prostaglandin analogs of the present invention include latanoprost,travoprost, uenoprost isopropyl ester, the free acids of those compoundsand other prostaglandin analogues known in the literature. Bimatoprostis actually a prostamide and is not a prostaglandin analog.

Compounds of the present invention may be represented generally by theformula I:

wherein the dashed bonds represent a single or double bond which can bein the cis or trans configuration, A is an alkylene or alkenyleneradical having from two to six carbon atoms, which radical may beinterrupted by one or more oxide radicals and substituted with one ormore hydroxy, oxo, alkyloxy or akylcarboxy groups wherein said alkylradical comprises from one to six carbon atoms;

B is a cycloalkyl radical having from three to seven carbon atoms, whichmay be unsubstituted or substituted with one selected from the groupconsisting of H, methyl, or perfluoromethyl, or an aryl radical,selected from the group consisting of hydrocarbyl aryl and heteroarylradicals having from four to ten carbon atoms wherein a heteroatom maybe selected from the group consisting of nitrogen, oxygen, halogenatoms, e.g. fluorine, lower alkyl radical having from one to six carbonatoms and optionally substituted with a halogen, and sulfur atoms;

X is a radical selected from the group consisting of —O(R⁴) and —N(R⁴)₂wherein R⁴ may be the same or different and is independently selectedfrom the group consisting of hydrogen, —CH₃, a lower alkyl radicalhaving from one to six carbon atoms optionally substituted with H or—CH₃, R⁵—C— or R⁵—O—C— wherein R⁵ is a lower alkyl radical having fromone to six carbon atoms;

Z is ═O or represents 2 hydrogen radicals; one of R₁ and R₂ is ═O, —OHor a —O(CO)R₆ group, and the other one is —OH or —O(CO)R₆, or R₁ is ═Oand R₂ is H, wherein R₆ is a saturated or unsaturated acyclichydrocarbon group having from 1 to about 20 carbon atoms, or —(CH₂)mR₇wherein m is 0 or an integer of from 1 to 10, and R₇ is cycloalkylradical, having from three to seven carbon atoms, or a hydrocarbyl arylor heteroaryl radical, as defined above, or apharmaceutically-acceptable salt thereof, provided, however, that when Bis not substituted with a pendant heteroatom-containing radical, and Zis ═O, then X is not —OR⁴. That is, the cycloalkyl or hydrocarbyl arylor heteroaryl radical is not substituted with a pendant radical havingan atom other than carbon or hydrogen.

Compounds of the present invention may also be represented by thefollowing general formula II:

wherein the dashed bonds represent a single or double bond which can bein the cis or trans configuration, wherein y is 0 or 1, x is 0 or 1 andx and y are not both 1, Y is a radical selected from the groupconsisting of alkyl, halogen, e.g. fluoro, chloro, etc., nitro, amino,thiol, hydroxy, alkyloxy, alkylcarboxy, halogen substituted alkyl suchas perfluoromethyl, perfluoroethyl and perfluoropropyl wherein saidalkyl radical comprises from one to six carbon atoms, and n is 0 or aninteger of from 1 to about 3 and R₃ is ═O, —OH or —O(CO)R₆ wherein R₆ isas defined above. Preferably, n is 1 or 2.

X is a radical selected from the group consisting of —O(R⁴) and —N(R⁴)₂wherein R⁴ may be the same or different and is independently selectedfrom the group consisting of hydrogen, —CH₃, a lower alkyl radicalhaving from one to six carbon atoms optionally substituted with H or—CH₃, R⁵—C— or R⁵—O—C— wherein R⁵ is a lower alkyl radical having fromone to six carbon atoms;

Z is ═O or represents 2 hydrogen radicals; one of R₁ and R₂ is ═O, —OHor a —O(CO)R₆ group, and the other one is —OH or —O(CO)R₆, or R₁ is ═Oand R₂ is H, wherein R₆ is a saturated or unsaturated acyclichydrocarbon group having from 1 to about 20 carbon atoms, or —(CH₂)mR₇wherein m is 0 or an integer of from 1 to 10, and R₇ is cycloalkylradical, having from three to seven carbon atoms, or a hydrocarbyl arylor heteroaryl radical, as defined above, or apharmaceutically-acceptable salt thereof, provided, however, that when Bis not substituted with a pendant heteroatom-containing radical, and Zis ═O, then X is not —OR⁴. That is, the cycloalkyl or hydrocarbyl arylor heteroaryl radical is not substituted with a pendant radical havingan atom other than carbon or hydrogen.

Compounds may also be represented by the general formula (III).

Compounds of the present invention may also be represented by thegeneral Formula (IV):

Or represented by the general Formula V:

In all of the above formulae, the dotted lines on bonds between carbons5 and 6 (C-5), between carbons 13 and 14 (C-13), between carbons 8 and12 (C-8), and between carbons 10 and 11 (C-10), indicate a single or adouble bond which can be in the cis or trans configuration. If two solidlines are used that indicates a specific configuration for that doublebond. Hatched lines at positions C-9, C-11 and C-15 indicate the αconfiguration. If one were to draw the β configuration, a solidtriangular line would be used.

y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y is a radicalselected from the group consisting of alkyl, halogen, e.g. fluoro,chloro, etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy,halogen substituted alkyl such as perfluoromethyl, perfluoroethyl andperfluoropropyl wherein said alkyl radical comprises from one to sixcarbon atoms, etc. and n is 0 or an integer of from 1 to about 3 and R₃is ═O, —OH or —O(CO)R₆ wherein R₆ is as defined above. Preferably, n is1 or 2.

X is a radical selected from the group consisting of —O(R⁴) and —N(R⁴)₂wherein R⁴ may be the same or different and is independently selectedfrom the group consisting of hydrogen, —CH₃, a lower alkyl radicalhaving from one to six carbon atoms optionally substituted with H or—CH₃, R⁵—C— or R⁵—O—C— wherein R⁵ is a lower alkyl radical having fromone to six carbon atoms;

Z is ═O or represents 2 hydrogen radicals; one of R₁ and R₂ is ═O, —OHor a —O(CO)R₆ group, and the other one is —OH or —O(CO)R₆, or R₁ is ═Oand R₂ is H, wherein R₆ is a saturated or unsaturated acyclichydrocarbon group having from 1 to about 20 carbon atoms, or —(CH₂)mR₇wherein m is 0 or an integer of from 1 to 10, and R₇ is cycloalkylradical, having from three to seven carbon atoms, or a hydrocarbyl arylor heteroaryl radical, as defined above, or apharmaceutically-acceptable salt thereof, provided, however, that when Bis not substituted with a pendant heteroatom-containing radical, and Zis ═O, then X is not —OR⁴. That is, the cycloalkyl or hydrocarbyl arylor heteroaryl radical is not substituted with a pendant radical havingan atom other than carbon or hydrogen.

In the compounds used in accordance with the present invention,compounds having the C-9 or C-11 or C-15 substituents in the α or βconfiguration are contemplated. As hereinabove mentioned, in allformulas provided herein broken line attachments to the cyclopentanering indicate substituents in the α-configuration. Thickened solid lineattachments to the cyclopentane ring indicate substituents in theα-configuration. Also, the broken line attachment of the hydroxyl groupor other substituent to the C-11 and C-15 carbon atoms signifies the αconfiguration.

For the purpose of this invention, unless further limited, the term“alkyl” refers to alkyl groups having from one to ten carbon atoms, theterm “cycloalkyl” refers to cycloalkyl groups having from three to sevencarbon atoms, the term “aryl” refers to aryl groups having from four toten carbon atoms. The term “saturated or unsaturated acyclic hydrocarbongroup” is used to refer to straight or branched chain, saturated orunsaturated hydrocarbon groups having from one to about 6, preferablyone to about 4 carbon atoms. Such groups include alkyl, alkenyl andalkynyl groups of appropriate lengths, and preferably are alkyl, e.g.methyl, ethyl, propyl, butyl, pentyl, or hexyl, or an isomeric formthereof.

The definition of R₆ may include a cyclic component, —(CH₂)_(m)R₇,wherein n is 0 or an integer of from 1 to 10, R₇ is an aliphatic ringfrom about 3 to about 7 carbon atoms, or an aromatic or heteroaromaticring. The “aliphatic ring” may be saturated or unsaturated, andpreferably is a saturated ring having 3-7 carbon atoms, inclusive. As anaromatic ring, R₇ preferably is phenyl, and the heteroaromatic ringshave oxygen, nitrogen or sulfur as a heteroatom, i.e. R₇ may be thienyl,furanyl, pyridyl, etc. Preferably m is 0 or an integer of from 1 to 4.

Z is ═O or represents two hydrogen atoms.

X may be selected from the group consisting of —O(R⁴) and —N(R⁴)₂wherein R⁴ may be the same or different and is independently selectedfrom the group consisting of hydrogen, —CH₃, a lower alkyl radicalhaving from one to six carbon atoms optionally substituted with H or—CH₃,

wherein R⁵ is a lower alkyl radical having from one to six carbon atoms.

1) Latanoprost

Latanoprost has the following structure:

Latanoprost is a prostaglandin analogue and is in fact a prodrug withits acid form (Latanoprost acid) being biologically active:

Latanoprost is an isopropyl ester, and is a prodrug which converts tolatanoprost free acid byr[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoic acid. The freeacid form of latanoprost is two-hundred times more potent thanlatanoprost as an FP receptor ligand for the human recombinant FPreceptor. Latanoprost free acid is a potent FP receptor agonist with anEC₅₀ of 3.6 nM for human FP receptors, which is twice the potency ofPGF_(2α). The efficacy of PG analog esters for the treatment of glaucomaor elevated IOP correlates closely with the FP receptor binding affinityof the free acid. Other forms of latanoprost which may be used in thepresent invention include 15-keto latanoprost, 15(S)-latanoprost,5-trans latanoprost, latanoprost-d4, latanoprost lactol and latanoprostethyl amide-d4.

Latanoprost is a molecule that is poorly dissolved in water but isgenerally fat soluble. Latanoprost is more fat soluble than bimatoprost.If an organic solvent-free solution of latanoprost is needed, it can beprepared by evaporating the methyl acetate and directly dissolving theneat oil in aqueous buffers. The solubility of latanoprost in PBS (pH7.2) is approximately 50 μg/mL. For maximum solubility in aqueousbuffers, latanoprost should first be dissolved in ethanol or propyleneglycol and then diluted with the aqueous buffer of choice. Latanoprosthas a solubility of 400 μg/mL in a 1:4 solution of ethanol:PBS (pH 7.2)using this method. In acidic or basic aqueous solutions, latanoprost isstable for no more than 48 hours and in neutral aqueous solutions it hasshown to be stable for up to one month at room temperature. Latanoprostis the isopropyl ester of 17-phenyl-13,14-dihydro prostaglandin F2a(17-phenyl-13,14-dihydro PGF2a).

Sufficient amount of solubility can be obtained even at the highestconcentration (5%) that can be used in propylene glycol, methanol,ethanol and 2-propanol. Moreover it has been noted that latanoprost canbe dissolved in a suitable dissolving agent such as alcohol (propyleneglycol, methanol, ethanol, 2-propanol) and other co-solvent such as somearomatic and polyhydric alcohols (cetyl alcohol, stearyl alcohol, benzylalcohol, glyceryl mono-oleate, POE stearate, polyoxyethylene laurylalcohol, 1-3butylene glycol, glycerol).

Latanoprost including 15-keto latanoprost, 15(S)-latanoprost, 5-translatanoprost, latanoprost-d4, latanoprost lactol, latanoprost ethylamide-d4 and latanoprost acid may be present in the formulations of thepresent invention in the following concentrations: 0.001%, 0.002%,0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%,0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, %, 0.11%, 0.12%,0.13%, 0.14%, 0.15%; 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%,0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%,0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%,0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%, 0.55%, 0.6%,0.65%, 0.7%, 0.75/o, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.2%, 1.3%,1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%,2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%,3.8%, 3.9, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%,5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%,18%, 19%, 20%, 21%, 22%, 23%, 24% and 25% w/w, w/v or v/v.

Latanoprost, including 15-keto latanoprost, 15(S)-latanoprost, 5-translatanoprost, latanoprost-d4, latanoprost lactol, latanoprost ethylamide-d4 and latanoprost acid may be present in the formulations of thepresent invention alone or in combination with other prostaglandinanalogs. Latanoprost including 15-keto latanoprost, 15(S)-latanoprost,5-trans latanoprost, latanoprost-d4, latanoprost lactol, latanoprostethyl amide-d4 and latanoprost acid may be present in the formulationsof the present invention alone or in combination with topical minoxidilor minoxidil sulphate or topical or oral finasteride. Latanoprost,including 15-keto latanoprost, 15(S)-latanoprost, 5-trans latanoprost,latanoprost-d4, latanoprost lactol, latanoprost ethyl amide-d4 andlatanoprost acid may be present in the formulations of the presentinvention alone or in combination with cyclosporine formulas I, II andIII.

2) Travoprost

Travoprost is a synthetic prostaglandin F analogue and isopropyl esterof the biologically active free acid. Its chemical name is [1R[1α(Z),2β(1E,3R*),3α,5α]]-7-[3,5-Dihydroxy-2-[3-hydroxy-4-[3(trifluoromethyl)phenoxy]-1-butenyl]cyclopentyl]-5-heptenoic acid,1-methylethylester. It has a molecular formula of C₂₆H₃₅F₃O₆ and amolecular weight of 500.55:

Travoprost free acid has the following structure:

Travoprost and travoprost free acid may be present in the formulationsof the present invention in the following concentrations: 0.001%,0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%,%, 0.11%.0.12%. 0.13%, 0.14%, 0.15%; 0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%,0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%,0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%,0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%, 0.55%,0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.2%,1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%,2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%,3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%,4.9%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% and 25% w/w, w/v or v/v.

Travoprost and travoprost free acid may be present in the formulationsof the present invention alone or in combination with otherprostaglandin analogs or other hair growth compounds. Travoprost andtravoprost free acid may be present in the formulations of the presentinvention alone or in combination with topical minoxidil or minoxidilsulphate or topical or oral finasteride. Travoprost and travoprost freeacid may be combined with cyclosporine formulas I, II or II.

3) Uenoprostone Isopropyl Ester

Unoprostone isopropyl ester has the following structure:

Uenoprostone isopropyl ester is a prodrug which converts to uenoprostonefree acid which has the following structure:

Uenoprostone isopropyl ester and uenoprostone free acid whileefficacious at lowering intraocular pressure, have been shown to causeno hair growth and in fact may inhibit hair growth (McCarey B. E., KapikB. M., Kane F. E. [2004]). Low incidence of iris pigmentation andeyelash changes in two randomized clinical trials was reported withuenoprostone isopropyl 0.15%. (Ophthalmology 111, 1480-1488). Thisdemonstrates that unpredictability of prostaglandin anologs for use ingrowing hair and that many prostaglandin analogs do not grow hair andmay inhibit hair growth.

4) Bimatoprost

Bimatoprost is a prostamide from a group of biological lipids, which arerelated to prostaglandins, but contain a terminal ethanolamide group andwhich target different receptors than prostaglandin analogues such aslatanoprost or travoprost. Technically, bimatoprost is not considered tobe a prostaglandin analog but is a prostamide. Bimatoprost may berepresented by the following formula:

Bimatoprost is not a prodrug and is not converted into another compoundor in only small amounts (under 5%) are believed converted intobimatoprost free acid. Bimatoprost differs from the other compounds inthat it is an amide:

While there is a bimatoprost free acid:

bimatoprost is believed to exert its biological activity as a hairgrowth agent as an ethyl amide and not as a free acid. This is incontrast to latanoprost and travoprost which are prodrugs and exerttheir physiological effects on different receptors than bimatoprostwhich illustrates the lack of predictability of bimatoprost,latanoprost, travoprost and uenoprostone isopropyl ester in their use instimulating hair growth. Bimatoprost and latanoprost have significantlydiffering solubilities and pharmacological properties. Bimatoprost saltforms include a tromethamine salt form. For example, LUMIGAN® 0.03% w/v,a topical solution for lowering elevated intraocular pressure andtreating glaucoma, the first approved use of bimatoprost, has a clinicalconcentration of bimatoprost of 0.03% w/v. XALATAN®, a topical solutionfor lowering elevated intraocular pressure and treating glaucoma, thefirst approved use of latanoprost, has a clinical concentration of0.005% w/v.

The action of prostamides such as bimatoprost involve mechanismsdifferent from prostanoid FP receptor-mediated responses with ligandssuch as latanoprost and travoprost. The effect of bimatoprost in monkeyswith elevated intraocular pressure model of glaucoma has been shown tobe additive to that of latanoprost (“Additivity of Bimatoprost orTravoprost to Latanoprost in Glaucomatous Monkey Eyes”, Gagliuso et al.,2004). Pharmacological distinctions between latanoprost and bimatoprosthave been demonstrated. Some human patients suffering from glaucoma whowere non-responsive to latanoprost were found responsive to bimatoprostin reducing elevated intraocular pressure (“Effect of bimatoprost onpatients with primary open-angle glaucoma or ocular hypertension who arenonresponders to latanoprost” Gandolfi 2003). It appears highly likelythat latanoprost and bimatoprost interact with different receptors inthe eye and in hair follicles.

Bimatoprost and bimatoprost free acid may be present in the followingconcentrations: 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%,0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,0.09%, 0.1%, %, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%; 0.16%, 0.17%, 0.18%,0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%,0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%,0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%,0.49%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%,1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%,2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%,3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%,4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% and 25% w/w,w/v or v/v.

Bimatoprost and bimatoprost free acid may be present in the formulationsof the present invention alone or in combination with otherprostaglandin analogs. Bimatoprost may be combined with topicalminoxidil or minoxidil sulphate or with topical or oral finasteride andmay be combined with cyclosporine I, II or III.

The following U.S. patents and patent publications are hereinincorporated by reference in their entireties: U.S. Pat. Nos. 8,038,988;6,262,105; 7,388,029; 6,403,649; 9,750,750; 9,149,484; 9,101,550;9,700,503; 6,946,120; 5,030,442; 5,030,442; 4,828,837; 7,803,357;7,749,489; 6,465,514; 4,596,812, 7,442,369; 5,620,980; 5,225,189;4,820,512; 6,596,266; and, 5,834,014.

U.S. Patent Publications 20160136071; 20160228345; 20050079139;20100210720; 20050079139; 20080206156; 20080206156; and, 20040082660.

B. Cyclosporines

Cyclosporine occurs naturally and was isolated from the fungusTolypocladin inflatum in 1971. Cyclosporine is an immunosuppressant andis used in Crohn's disease, nephrotic syndrome, rheumatoid arthritis, inorgan transplants to prevent rejection and treatment of dry eye disease.Cyclospormes are a group of nonpolar cyclic oligopeptides with knownimmunosuppressant activity. Cyclosporine A, along with several otherminor metabolites, as well as cyclosporine B, C, D, E, F, G, H, I, J, K,L, M, N, O, P, Q, R, S, T, U, V, W, X, Y and Z, have been identified. Inaddition, derivatives, salts and the like of such cyclosporines and anumber of synthetic analogs have been prepared and may be useful in thepresent invention. The use of cyclosporine A and cyclosporine Aderivatives to treat various ophthalmic conditions, has been the subjectof various patents, for example U.S. Pat. Nos. 5,474,979; 6,254,860;6,350,442; and 7,368,436, the disclosure of each of which areincorporated by reference in their entireties.

In general, commercially available cyclosporines may contain a mixtureof several individual cyclosporines which all share a cyclic peptidestructure consisting of eleven amino acid residues with a totalmolecular weight of about 1,200 Daltons, but with different substituentsor configurations of some of the amino acids. Thus the present inventionalso contemplates mixtures of different types of cyclosporine orcyclosporine components. The term “cyclosporine component” as usedherein is intended to include any individual member of the cyclosporinegroup, salts thereof, derivatives thereof, analogs thereof and mixturesthereof, as well as mixtures of two or more individual cyclosporinessalts thereof, derivatives thereof analogs thereof and mixtures thereof.

Particularly preferred cyclosporine components include, withoutlimitation, cyclosporine A, derivatives of cyclosporine A, salts ofcyclosporine A and the like and mixtures thereof. Cyclosporine A is anespecially useful cyclosporine component.

The chemical structure for cyclosporine A is represented by Formula 1:

As used herein, the term “derivatives” of a cyclosporine refer tocompounds having structures sufficiently similar to the cyclosporine soas to function in a manner substantially similar to or substantiallyidentical to the cyclosporine, for example, cyclosporine A, in thepresent compositions and methods. Included, without limitation, withinthe useful cyclosporine A derivatives are those selected from((R)-methylthio-Sar)³-(4′-hydroxy-MeLeu) cyclosporine A,((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporine A, and((R)-(Cyclo)alkylthio-Sar)³-cyclosporine A derivatives described below.

These cyclosporine derivatives are represented by the followinggeneralformulas (II) and (III), respectively:

wherein Me is methyl; Alk is 2-6C alkylene or 3-6C cycloalkylene; R isOH, COOH, alkoxycarbonyl, —NR₁R₂ or N(R₃)—(CH₂)—NR₁R₂; wherein R₁, R₂ isH, alkyl, 3-6C cycloalkyl, phenyl (optionally substituted by halo,alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino), benzyl orsaturated or unsaturated heterocyclyl having 5 or 6 members and 1-3heteroatoms; or NR₁R₂ is a 5 or 6 membered heterocycle which may containa further N, O or S heteroatom and may be alkylated; R₃ is H or alkyland n is 2-4; and the alkyl moieties contain 1-4C.

The present compositions and methods may be practiced employing anysuitable compositions or combinations of compositions includingtherapeutically effective amounts of cyclosporine component inconjunction with bimatoprost, latanoprost, latanoprost acid andtravoprost and travoprost free acid useful to promote hair growth. Thecyclosporine component is present in an amount and/or concentrationeffective enough to provide the desired therapeutic effect when thecyclosporine-containing composition is administered to a human or animalin accordance with the present invention. Mixtures of cyclosporinecomponents are contemplated. In one embodiment of the invention, thecyclosporine component advantageously is present in the compositions inamounts ranging from about 0.01-0.05% w/v, 0.05-0.1% w/v, 0.1% to about0.5% w/v, 0.5%-5% w/v, 5%-15% w/v, and 15% or about 20% or 25% w/v ofthe composition.

In another embodiment, the cyclosporine component is present in anamount of about 0.01% to about 5% or about 10% or about 15% by weight ofthe composition. Cyclosporine may be present in the followingconcentrations: 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%,0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,0.09%, 0.1%, %, 0.11%, 0.12%. 0.13%, 0.14%, 0.15%; 0.16%, 0.17%, 0.18%,0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%,0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%,0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%,0.49%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%,1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%,2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%,3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%,4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10%, 11%, 12%,13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% and 25% w/w,w/v or v/v.

Cyclosporine, both topical and oral, in all its various forms may bepresent in combination with bimatoprost, latanoprost, latanoprost acid,travoprost, travoprost free acid, minoxidil, minoxidil sulphate and oralor topical finasteride.

C. Other Hair Growth Agents

1) Minoxidil:

Minoxidil is believed to open adenosine triphosphate (ATP)-sensitivepotassium channels and vasodilates blood vessels allowing morenutrients, blood and oxygen into the follicles. In the late telogenphase of the hair follicle growth cycle, stem cells located in the bulgeregion differentiate and re-enter anagen phase. In patients sufferingfrom androgenetic alopecia hair follicles become smaller and anagenphase is shortened in duration. Minoxidil increases the amount ofintracellular Ca2+, which may upregulate the enzyme adenosinetriphosphate (ATP) synthase, independent of its role in ATP synthesis,and promotes stem cell differentiation. It is theorized that minoxidilinduced Ca2+ influx can increase stem cell differentiation and may be afactor in the mechanism by which minoxidil facilitates hair growth(Mechanism of Action of Minoxidil in the Treatment of AndrogeneticAlopecia . . . ), A. Gren et al., J Biol Regul Homeost Agents 31(4):1049-1053 (2017).

There is some evidence that minoxidil may cause hair in the telogenphase to shed, which are replaced by newer and thicker hairs in theanagen phase. Minoxidil is a prodrug which converts to minoxidilsulphate by the sulfotransferase enzyme SULT1A1.

Further, minoxiddl sulphate as compared to minoxiddl is a much morepotent hair growth agent. Some studies speculate that the amount ofenzyme SULT1A1 in and around the hair follicles is what determineswhether individuals respond well to minoxidil. Minoxidil can be combinedwith bimatoprost, latanoprost, 15-keto latanoprost, 15(S)-latanoprost,5-trans latanoprost, latanoprost-d4, latanoprost lactol, latanoprostethyl amide-d4 and latanoprost acid, travoprost and travoprost free acidwhich in theory causes entry into the anagen phase more quickly andlengthens the anagen phase. Minoxidil can also be combined withcyclosporine. Minoxidil can be combined with those compounds at thefollowing concentrations: 0.001%, 0.002%, 0.003%, 0.004%, 0.005%,0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.1%, %, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%;0.16%, 0.17%, 0.18%, 0.19%, 0.2%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%,0.26%, 0.27%, 0.28%, 0.29%, 0.3%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%,0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%,0.46%, 0.47%, 0.48%, 0.49%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%,0.85%, 0.9%, 0.95%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%,1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%,3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9, 4.0%, 4.1%,4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5.0%, 5.5%, 6.0%, 6.5%,7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% and 25% w/w, w/v or v/v.

2) Finasteride

Finasteride (C₂₃H₃₆N₂O₂), also known as(1S,3aS,3bS,5aR,9aR,9bS,11aS)-N-tert-butyl-9a,11a-dimethyl-7-oxo-1,2,3,3a,3b,4,5,5a,6,9b,10,11-dodecahydroindeno[5,4-f]quinoline-1-carboxamide,is a 5α-reductase inhibitor originally used to treat enlarged prostatesin males. Oral finasteride works by decreasing the production ofdihydrotestosterone (DHT) by about 70%, including in the prostate glandand the scalp. There have been some reports of success in growing scalphair using topical finasteride. Finasteride can be combined with theprostaglandin analogs of the present invention including bimatoprost,latanoprost and travoprost and their analogs.

Finasteride can be combined with bimatoprost, latanoprost, 15-ketolatanoprost, 15(S)-latanoprost, 5-trans latanoprost, latanoprost-d4,latanoprost lactol, latanoprost ethyl amide-d4 and latanoprost acid,travoprost and travoprost acid which in theory causes entry into anagenphase more quickly and lengthens anagen phase. Finasteride can becombined with minoxidil, minoxidil sulphate or cyclosporine. Finasteridecan be combined with those compounds at the following concentrations:0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%,0.0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%,%, 0.11%, 0.12%. 0.13%, 0.14%, 0.15%; 0.16%, 0.17%, 0.18%, 0.19%, 0.2%,0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.3%,0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%,0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1.0%, 1.1%,1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%,2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%,3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%,4.8%, 4.9%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%,10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%,24% and 25% w/w, w/v or v/v.

Definitions

The term “about” refers to slight variations in the concentrations ofactive agents or excipients that a regulatory agency such as the FDA orEMEA would find to be bioequivalent.

The term “aerosol foam” is a product, which includes a liquid foamablecomposition and a propellant liquid, filled into a pressurized containerthat is equipped with a valve system and nozzle at the top of thecontainer, and a dip tube that runs from the valve system to the bottomof the container. When the valve is open, the pressure on the liquidpropellant is instantly reduced and it starts to evaporate forming ahigh-pressure gas layer at the top of the container. This high-pressuregas layer pushes the liquid product, as well as some of the liquidpropellant, up the dip tube and out through the nozzle. When the liquidsflow through the nozzle, the liquid propellant evaporates into gas andin the process forms propellant gas bubbles in the liquid productcreating foam.

An “effective amount” of a compound is an amount sufficient tocontribute to the treatment, prevention, or reduction of a symptom orsymptoms of a disease. Where recited in reference to a diseasetreatment, an “effective amount” may also be referred to as a“therapeutically effective amount.” A “reduction” of a symptom orsymptoms (and grammatical equivalents of this phrase) means decreasingof the severity or frequency of the symptom(s), or elimination of thesymptom(s). A “prophylactically effective amount” of a drug orformulation is an amount of a drug or formulation that, whenadministered to a subject, will have the intended prophylactic effect,e.g., preventing or delaying the onset (or reoccurrence) a disease,disorder or condition, or reducing the likelihood of the onset (orreoccurrence) of a disease, disorder or condition or symptoms thereof.The full prophylactic effect does not necessarily occur byadministration of one dose, and may occur only after administration of aseries of doses. Thus, a prophylactically effective amount may beadministered in one or more administrations.

“Emulsion” refers in the customary sense to a mixture of two or moreimmiscible liquid components, one component (e.g., a therapeutic lipiddescribed herein or mixture thereof including surfactant) beingdispersed through the other component (e.g., the aqueous component of acomposition described herein). The term “sub-micron emulsion” refers toan emulsion containing components having an extent in the longestdimension of less than about 1 micron.

“Growing hair” or “grow hair” refers to causing hair growth to increaseas compared to the rate of hair growth without applying the drugs and/orformulations of the present invention.

“Hairs” may be vellus hairs which are fine, thin, non-pigmented shorthairs in which the hair bulb is located superficially in the dermis.Intermediate hairs that are in a growth stage between vellus (“baby” orimmature) hair, such as on your face, and mature hair stage of growthsuch as the hair on the scalp. Terminal hairs are coarse, pigmented,long hairs in which the bulb of the hair follicle is seated deep in thedermis. As alopecia progresses, a transition takes place in the area ofapproaching baldness wherein the hairs themselves are changing from theterminal to the vellus type.

“Hair loss” may refer to alopecia areata, androgenetic alopecia, malepattern hair loss, female pattern hair loss, telogen effluvium, anageneffluvium, tinea capitis, cicatricial alopecia, lichen planopilaris,discoid lupus erythematsus, folliculitis decalvans, dissectingcellulitis of the scalp, central centrifugal cicatricial alopecia,frontal fibrosing alopecia, loose anagen syndrome, hair shaftabnormalities, involutional alopecia, androgenic alopecia,trichotillomania, hair loss due to chemotherapy, hair loss due toinfectious agents, trichorrhexis nodosa and senescent alopecia.

“Locale of hair follicles” means an area of skin (scalp, brow, eyelidmargins, face, etc.) containing hair follicles.

“Non-aerosol, non-spray foam” is a product, which comprises a foamableliquid composition, which is filled into a non-pressurized containerthat is equipped with a mechanical pump, an air chamber, a mixingchamber, a foam forming screen mesh, and a dip tube that runs from themechanical pump to the bottom of the container. When the mechanical pumpis actuated, the foamable liquid composition is forced up the dip tubeinto the mixing chamber where it is comingled with air from the airchamber, at a predetermined ratio to form foam. It is the actuation ofthe pump that pressurizes and causes the turbulent comingling of the airand the liquid foamable composition to form air bubbles in the foamableliquid composition creating foam. From the mixing chamber, the foam isthen homogenized into fine uniform bubbles when it passes through thescreen mesh before being dispensed out through the nozzle. Therefore, itis a non-propellant method of propelling the liquid product out of thecontainer in the form of foam. A major difference in the continuousstate of the containers is that in an aerosol foam container thepropellant fluid (typically compressed gas or liquefied gas) is pumpedinto the container under high pressure after the container is sealed andis maintained continuously in pressurized state, whereas in starkcontrast in the container of the non-aerosol, non-spray foam, the airinside the container is constantly under atmospheric pressure.

A “pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” means a carrier or an excipient that is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable, and includes a carrier or anexcipient that is acceptable for veterinary use as well as humanpharmaceutical use. “A pharmaceutically acceptable carrier/excipient” asused in the specification and claims includes both one and more than onesuch excipient.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like. See e.g., Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19). Additional information onsuitable pharmaceutically acceptable salts can be found in REMINGTON'SPHARMACEUTICAL SCIENCES, 17th ed., Mack Publishing Company, Easton, Pa.,1985, which is incorporated herein by reference. Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

“Preventing hair loss” means slowing down or preventing hair loss thatwould occur as compared to if a formulation of the present invention wasnot applied.

The methods and compositions of the present invention of the presentinvention can be used to prevent hair loss, to treat hair loss, to treator thicken thinning hair, to treat loss of eyebrows, to treat loss ofeyelashes or facial hair, and can be used to treat all types ofalopecia, convert vellus hair to terminal hair or increase melanincontent in hair by turning the hair darker or increasing the ratio ofdark hair to grey hair on the scalp, eyebrows, eyelashes or facial hair.

The term “prodrug” is used according to its plain ordinary meaning andis intended to mean compounds that require a chemical or enzymatictransformation in order to release the active parent drug in vivo priorto producing a pharmacological effect.

The term “soluble” refers the ability of the solvent to dissolve anamount of the active pharmaceutical ingredient that is relevant for itspharmacological effect.

The terms “solvent” and “solvent system” define one component of theformulation, the liquid or semi-solid phase that contains the API.

The terms “stable” and “stability” are used here in relation to theshelf-life of a pharmaceutical product, and are related to the physicalchange, degradation or chemical decomposition of active pharmaceuticalingredients or formulation, which limits the shelf-life of a product.

“Synergism” between two drugs, for example in a fixed combination, canoccur when the two drugs interact in a manner that enhance or magnifyone or more effects, or with two different mechanisms of actions whichwhen combined result in a greater therapeutic affect or efficacy thaneither drug applied alone or the two drugs serially, or avoid or lowerunwanted side effects when the drugs are provided as monotherapies, ofthose drugs. Negative effects of synergy are a form of contraindicationsuch as when more than one depressant drug is used that affects thecentral nervous system (CNS), an example being alcohol and Valium.“Synergism” has also been noted in describing how complex systemsoperate. For example, biological systems may react in a non-linear wayto perturbations, so that the outcome may be greater than the sum of theindividual component alterations.

In describing the present invention, synergism means that thecombination of the two active drugs, utilized in the methods andcompositions of the invention achieves a result, e.g. stimulating thegrowth of hair such as scalp hair, eyebrows or eyelashes, in a mammal,e.g. a human, that is greater than the result achieved when the activedrugs are utilized, alone as monotherapies, under the same conditions.Thus, to determine the combinations that are within the scope of thepresent invention, one may simply compare the result achieved by thecombination of the two drugs with the result achieved with each of theindividual drugs, alone.

The term “topical” in the context of methods described herein relates inthe customary sense to the administration of a compound orpharmaceutical composition which is incorporated into a suitablepharmaceutical carrier and administered at a topical treatment site of asubject. Accordingly, the term “topical pharmaceutical composition”includes those pharmaceutical forms in which the compound isadministered externally by direct contact with a topical treatment site,e.g., the skin, scalp, brow, eyelid margins, face. The term “topicalepidermal pharmaceutical composition” refers to a pharmaceuticalcomposition suitable for administering directed to the epidermal layerof the skin, e.g., the palpebra, the supercilium, the scalp, or thebody. The term “topically administering” refers to administeringexternally by direct contact with a topical treatment site. The term“topical epidermal administering” refers to administering externally bydirect contact with the epidermis.

The terms “treat” “treating” or “treatment” may refer to any indicia ofsuccess in the treatment or amelioration of an injury, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or computerized imaging systems. Forexample, the certain methods presented herein successfully treat hairloss by decreasing the incidence of hair loss, in inhibiting itssymptoms and or cause and causing new hair growth.

Anatomy of Hair and Hair Growth

Orifices of hair follicles occupy only about 0.1% of the total skinsurface area of humans, while hair follicles can occupy as much as 10%of the total surface area on the human scalp (Schaefer, H., et. al.(1990) “Follicular penetration” (pgs. 163-173)(1990). In general,follicular openings lead to epithelial surfaces that do not have theprotective stratum corneum of surface skin. Consequently, hair folliclesand sebaceous glands contribute significantly to transdermal drugdelivery. Consequently, hydrophilic drugs can penetrate with high fluxand usually through the intrafollicular routes, along the junction ofthe internal and external route sheath, and rapid diffusion into thedermis by the outer route sheath. Longer lag times for the scalp skinpenetration of hydrophilic drugs, as compared to the shorter time forlipophilic drugs, suggest that the permeation of hydrophilic drugs viathe upper dermis is a rate-limiting step. The penetration routes oflipophilic drugs is probably along the junction of internal and externalroot sheath.

Release of sebum by sebaceous glands associated with the hair follicleforms a lipoidal pathway for lipophilic materials in the follicles(Ebling et al., 1991).

It is also believed that a penetration route for lipophilic permeants isthe transepidermal pathway. Thus, the penetration through the stratumcorneum of scalp skin is also an important pathway but some drugs mayuse the trans follicular route. Sebum located in the follicles alsoplays an important role in drug penetration in the outer root sheath.Human hair follicles can vary in diameter from 5 um to 80 um, which canaffect trans-follicular penetration.

Certain penetration enhancers and solvents help fluidize lipids, inintercellular channels of the stratum corneum. Penetration of permeantsand drugs through the scalp skin, is believed to be related to the rapidpermeation into the hair follicles and the rapid diffusion through theouter root sheath, into the dermis, whereas the trans epidermalpermeation of drugs is largely via the microchannels. Hydrophilic drugsalso rapidly diffused into the dermis via the outer root sheath, butpermeation of hydrophilic drugs via the upper dermis may berate-limiting step and relatively slow.

Human scalp anagen hair follicles are believed to express the genes andprotein for prostanoid receptors in the dermal papillae and the CTSsurrounding the hair bulb, but not in the epithelial keratinocytes orthe melanocytes of the hair bulb. One theory is that some prostaglandinanalogues bind to specific receptors on the plasma membrane of cells inthe regulatory dermal papilla in the hair bulb, which probablystimulates intracellular signaling pathways, resulting in hair growthand the lessening of hair loss. For example, although not wishing to bebound to any theory, prostaglandin analogs such as latanoprost mayincrease the number of hairs in the anagen phase by shifting hairs fromthe resting telogen phase to the anagen phase, shortening the time tobegin the anagen phase and lengthening the anagen phase, which causeshair to grow longer. In patients suffering from androgenetic alopecia,the anagen phase is reduced in duration and follicles spend more time inthe telogen phase as compared to patients not suffering fromandrogenetic alopecia. Latanoprost, travoprost and bimatoprost, invarying degrees, may also stimulate melanogenesis in melanocytes andkeratogenesis found in the dermal papilla which results in darker hair,with more melanin expressed in the individual hair and also increasesthe individual hair diameter and the size of the dermal papilla, whichin turn results in an increase in number of hairs which are longer,darker and thicker than hairs would be if not being treated withlatanoprost, travoprost and bimatoprost. And while it has been reportedthat bimatoprost may induce certain signals in the dermal papilla whichaccounts for its use in growing eyelashes, bimatoprost, which is aprostamide, is believed to have a separate receptor system fromprostaglandin analogs and therefore a differing mechanism of action(Khidir, “The Prostamide-related glaucoma therapy . . . ” FASEB, 27[2]:557-567 [February 2013]).

Keratinocyte cells are found in the outermost layer of the skin known asthe epidermis. Keratinocyte cells are also found in the basal layer ofskin. Keratinocyte cells make up about 95% of the epidermis.Keratinocytes undergo keratinization and form the superficial layer ofskin. These superficial keratinized cells are continuously replaced bycells derived from mitotic cells in the lowest layer of the epidermiswhich is the basal layer. The cells in the basal layer are sometimescalled basal keratinocytes or basal cells. The epidermis is about 0.2 mmthick. Inside the epidermis, keratinocytes are arranged in fourdifferent layers known as the stratum basale, stratum spinosum, stratumgranulosum, and stratum corneum. Melanocytes located in the basal layerdo not undergo keratinization but produce melanin. Melanin accumulatesin small granules known as melanosomes which are transported todendrites and then transferred to keratinocytes. Keratinocytes andmelanocytes are located in hair follicles along with dermal fibroblasts.Homeostasis of the epidermis and hair follicle is primarily regulated bythe cellular interaction between keratinocytes and melanocytes.Keratinocytes stimulate melanocyte functions such as melanogenesis,proliferation, differentiation and dendritogenesis through paracrinesignaling from cell to cell. Hirobe, “Keratinocytes Regulate theFunction of Melanocytes” Dermatolgica Sinica. Vol. 32, pgs. 200-204(2014). It is theorized that prostaglandin analogs such as latanoprostor travoprost may act on keratinocytes, which make hair, and melanocyteswhich produce pigment. It is possible that prostaglandin analogs actdirectly upon keratinocytes to make individual hairs thicker in diameterand melanocytes to make hair the hair darker or rather, the normal haircolor of the individual user. It is also possible that this occursthrough indirect action via the dermal papilla, which is located at thecenter of the hair bulb at the follicular base, by paracrine signals tothe keratinocytes and/or melanocytes which is a result of an undefinedfollicular signaling system.

Eyebrows

Loss of eyebrow hair, also known as madarosis, is characterized by alack of growth or loss of eyebrow hair. Loss of eyebrow hair can havecosmetic, functional, and social/psychological consequences. Accordingto the research, the diameter of scalp hair is normally thicker thaneyebrow hair in Asian patients, while the reverse is true in Caucasianpatients (Gandelman M. A Technique for Reconstruction of Eyebrows andEyelashes. Semin Plast Surg. 19:153-8 (2005)). Eyebrow hair is generallyless dense laterally than medially which results in hair loss in theeyebrows and brings more noticeable in the lateral portion. Eyebrows canbe roughly divided into three areas. The medial third is usually belowthe orbital margin with the hairs in this region oriented vertically.The middle third lies along the orbital margin with hairs orientedobliquely or horizontally. The lateral third usually lies above theorbital margin.

Madarosis of the eyebrows can be caused by disease such asdermatological diseases, endocrinopathy, such as thyroid disease and dueto psychological disorders such as trichotillomania and chemotherapy.Heredity can also play a factor in conditions such as congenitalaplasia. Madarosis of the eyebrows can by physical trauma such as burns,complications with cosmetic procedures such tattooing and complicationsfrom implantation.

Eyelashes

Eyelashes serve a functional and protective mechanism by protecting theeye by keeping foreign particles and objects from entering the eye. Longeyelashes are considered generally to be more attractive than shorteyelashes across most cultures. The nervous system surrounding the eyeis more easily excited to protect the eyes in most mammals. Loss ofeyelashes is known as hypotrichosis of the eyelashes which includesidiopathic hypotrichosis, chemotherapy induced hypotrichosis, alopeciaareata and hypothyroidism. Eyelash length is largely proportional to agewith younger people having longer eyelashes and older people havingshorter eyelashes. Current treatment for hypotrichosis of the eyelashesincludes LATISSE® which is a 0.03% w/v bimatoprost solution and isapplied to the upper eyelid margin.

Chemotherapy

Chemotherapy induced alopecia occurs mainly because the chemotherapeuticagent damages the hair follicle resulting in total or incomplete hairloss. Hair loss occurs in approximately 65% of chemotherapeuticpatients. Loss of hair is generally all over the body and is not limitedto the scalp and include eyelashes and eyebrows. Hair loss due tochemotherapy can be psychologically devastating and has been describedby some patients as a constant reminder of their illness and can resultin feelings of loss of control and increased social isolation(Beisecker, Analee et al., Side Effects of Adjuvant Chemotherapy,Pycho-Oncology, 1997, 83-93-6). Focus groups have also demonstrated thatthe loss of eyelashes and eyebrow hair was psychologically moredevastating than loss of scalp hair.

Other non-chemotherapy drugs can also cause hair loss such asanticoagulants, oral contraceptives, retinoids, antithyroid drugs andinterferons. Generally, chemotherapy-induced hair loss results fromtoxicity to rapidly dividing cells in the hair follicle. During anagen,the epithelial compartment of the hair follicle undergoes rapidproliferation, with the greatest proliferation in the bulb matrix cells.When chemotherapeutic agents are administered to a patient, cell mitosiscan abruptly stop resulting in hair loss because the partiallykeratinized hair shaft weakens and leads to the hair falling out. Thisis known as anagen effluvium. Chemotherapeutic agents can also causeapoptosis (programmed cell death) to cells in the hair follicle. Ingeneral, when chemotherapy is ended, hair growth returns but in somepatients it can take years or several complete hair cycles to achievethe same level of hair growth the patient was experiencing prior tochemotherapy. Generally, the new hair is vellus hair rather thanterminal hair. The formulations and methods described in thespecification can be used before or during chemotherapy on the scalp,face, eyebrows, eyelashes and all over the body to prevent loss of hairand also after chemotherapy to regrow hair and shift the hair cycle intoanagen phase and lengthens anagen phase resulting in longer, darker andthicker eyelashes, eyebrows, scalp hair and facial hair.

Vehicles

TABLE 1 list solvents and penetration enhancers: Capmul 808G EP/NFGlyceryl Monocaprylate 26402-26-6 Capmul GDB EP/NF* Glyceryl Dibehenate94201-62-4 Capmul GMO-50 EP/NF Glyceryl Monooleate 25496-72-4 Capmul MCMC8 EP/NF Glyceryl Monocaprylate 26402-26-6 Capmul MCM EP/NF GlycerylCaprylate/Caprate 91744-32-0, or 26402-22-2, and 26402-26-6 Capmul INJMCM EP/NF Glyceryl Caprylate/Caprate 91744-32-0, or 26402-22-2 and26402-26-6 CAPMUL INJ MCM EP Glyceryl Caprylate/Caprate 91744-32-0, or26402-22-2, and 26402-26-6 Capmul PG-2L EP/NF Propylene Glycol Dilaurate22788-19-8 Capmul PG-8 NF Propylene Glycol Monocaprylate 68332-79-6, or31565-12-5 Capmul PG-8-70 NF Propylene Glycol 68332-79-6 Monocaprylate,NF Type 1 Capmul PG-12 EP/NF Propylene Glycol Monolaurate 27194-74-7CAPTEX ® 170 EP Coco-Caprylate/Caprate 95912-86-0 CAPTEX 200P PropyleneGlycol Dicaprylocaprate 68583-51-7 CAPTEX 300 EP/NF GlycerylTricaprylate/Tricaprate 65381-09-1 CAPTEX INJ 300 LOW C6 GlycerylTricaprylate/Tricaprate 65381-09-1, or 73398-61-5 EP/NF/JPE CAPTEX 355EP/NF/JPE Glyceryl Tricaprylate/Tricaprate 65381-09-1, or 73398-61-5CAPTEX INJ 355 EP/NF/JPE Glyceryl Tricaprylate/Tricaprate 65381-09-1, or73398-61-5 CAPTEX 8000 Glyceryl Tricaprylate, Tricaprylin 538-23-8CAPTEX INJ 8000 NP Glyceryl Tricaprylate, Tricaprylin 538-23-8 Captex100 Propylene Glycol Dicaprate 53824-77-4 Captex 170 Caprylic/CapricAcid Ester of 95912-86-0 Saturated Fatty Alcohol C12-C18 Captex GTOTriolein 122-32-7 Captex NPGC Decanoic acid, mixed esters with neopentylglycol and octanoic acid CAPTEX INJ 300 LOW GlycerylTricaprylate/Tricaprate 65381-09-1, or 73398-61-5 C6 EP/NF/JPE CAPTEXINJ 355 EP/NF/JPE Glyceryl Tricaprylate/Tricaprate 65381-09-1, or73398-61-5 CAPTEX INJ 8000 NP Glyceryl Tricaprylate, Tricaprylin538-23-8 Capmul INJ MCM EP* Caprylic capric mono- & 91744-32-0, or26402-22-2, diglycerides and 26402-26-6 Acconon INJ MC8-2 EP/NF* PEG-8caprylic/capric glycerides 91744-32-0, 223129-75-7 CremerCOOR ® MCT60-40 Caprylic/Capric Triglyceride 65381-09-1 CremerCOOR ® MCT 70-30Caprylic/Capric Triglyceride 65381-09-1 CremerCOOR ® EHC 2-EthylhexylCocoate 92044-87-6 CremerCOOR ® EHL 2-Ethylhexyl Laurate 20292-08-4CremerCOOR ® EHP 2-Ethylhexyl Palmitate 29806-73-3 CremerCOOR ® EHS2-Ethylhexyl Stearate 91031-48-0 CremerCOOR ® GMS 40/ Glycerol stearate67701-33-1 SE (self-emulsifier) CremerCOOR ® IPM Isopropyl Myristate110-27-0 CremerCOOR ® IPP Isopropyl Palmitate 142-91-6 CremerCOOR ®Triacetin Glycerol Triacetate 102-76-1 1,2-DIMYRISTOYL-SN- 18194246GLYCERO-3-PHOSPHOCHOLINE DIISOPROPANOLAMINE 110974 DIISOPROPYL ADIPATE6938949 DIPROPYLENE GLYCOL 25265718 FATTY ACID ESTERS (Medium and shortchain) MYRISTYL ALCOHOL 112721 N,N-DIMETHYLACETAMIDE 127195 POLYOXYL 35CASTOR OIL 61791126 POLYOXYL 40 STEARATE 9004993 POLYOXYL 40HYDROGENATED 61788850 CASTOR OIL

The solvents and penetration enhancers may be present in the followingconcentrations: 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%,0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%,1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%,2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%,3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7%,4.8%, 4.9%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10% w/w, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%,43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%,85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99% w/w, w/v or v/v of the formulation.

Carbomer may be at a concentration of about 0.05-3.0% w/w, isopropylmyristate at a concentration of about 0.1 to about 10% w/w; PEG 40castor oil at a concentration of about 0.1 to 20% w/w; carboxymethylcellulose from 0.1-5.0% w/w ethanol about 1 to about 70% w/w; diethyleneglycol monoethyl ether at a concentration of about 1.0 to about 50% w/w;polysorbate 20 at a concentration of about 0.1 to about 5.0% w/w;polysorbate 40 at a concentration of about 0.1 to about 5.0% w/w;polysorbate 60 at a concentration of about 0.1 to about 5.0% w/w;glycerin at a concentration of about 1.0 to about 30% w/w; polysorbate80 at a concentration of about 0.1 to about 5.0% w/w; PPG-5 ceteth-20 ata concentration of about 0.1 to about 5.0% w/w; oleic acid at aconcentration of about 0.1 to about 5.0% w/w; isostearyl isostearate ata concentration of about 0.1 to about 10% w/w; dipropylene glycoldimethyl ether at a concentration of about 1 to about 50% w/w;diethylene glycol at a concentration of about 1 to about 50% w/w;dipropylene glycol at a concentration of about 1 to about 50% w/w;caprylic/capric at a concentration of about 0.1 to about 10% w/w; benzylalcohol at a concentration of about 0.1 to about 2.0% w/w; silicone at aconcentration of about 0.1 to about 10% w/w; PEG 40 castor oil at aconcentration of about 0.1 to 20% w/w; PEG 35 castor oil at aconcentration of about 0.1 to 20% w/w; oleyl alcohol at a concentrationof about 0.1 to 10% w/w; glyceryl monooleate at a concentration of about0.1 to 10% w/w; and/or water at a concentration of about 0 to about 90%w/w.

EXAMPLES

Formulation I

0.05% w/v latanoprost;

0.06% w/v cyclosporine A;

10.0% w/v diethylene glycol monoethyl ether;

5.0% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation II

0.08% w/v latanoprost;

0.1% w/v cyclosporine A;

15.0% w/v diethylene glycol monoethyl ether;

5% w/v PEG;

6.0% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation III

0.08% w/v latanoprost;

0.1% w/v cyclosporine A;

15.0% w/v diethylene glycol monoethyl ether;

5% w/v PEG;

6.0% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation IV

0.06% w/v bimatoprost;

0.08% w/v cyclosporine A;

10.0% w/v glyceryl monooleate;

5.0% w/v oleic acid;

5% w/v ethanol; and,

q.s. water 100%.

Formulation V

0.08% w/v bimatoprost;

0.1% w/v cyclosporine A;

10.0% w/v diethylene glycol monoethyl ether;

5.0% w/v oleic acid;

5.0% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation VI

0.08% w/v latanoprost or latanoprost acid;

0.08% w/v cyclosporine A;

10.0% w/v polyethylene glycol;

10.0% w/v diethylene glycol monoethyl ether;

5.0% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation VII

0.05% w/v bimatoprost;

0.07% w/v cyclosporine A;

10.0% w/v oleyl alcohol;

10.0% w/v diethylene glycol monoethyl ether; and,

q.s. water 100%.

Formulation VIII

0.05% w/v latanoprost or latanoprost acid;

0.08% w/v cyclosporine A;

5.0% w/v diethylene glycol monoethyl ether;

10.0% w/v CAPTEX 300 EP/NF;

10.0% w/v PEG; and,

q.s. water 100%.

Formulation IX

0.06% w/v uenoprostone isopropyl ester free acid;

0.08% w/v cyclosporine A;

5.0% w/v diethylene glycol monoethyl ether;

10.0% w/v CAPTEX 300 EP/NF;

10.0% w/v PEG; and,

q.s. water 100%.

Formulation X

0.07% w/v travoprost or travoprost free acid;

0.08% w/v cyclosporine A;

5.0% w/v diethylene glycol monoethyl ether;

10.0% w/v CAPTEX 300 EP/NF;

10.0% w/v PEG; and,

q.s. water 100%.

Formulation XI

0.1% w/v bimatoprost;

005% w/v cyclosporine A;

20% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and,

q.s. water 100%.

Formulation XII

0.1% w/v latanoprost;

005% w/v cyclosporine A;

20% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and

q.s. water 100%.

Formulation XIII

0.1% w/v latanoprost;

5.0% w/v minoxidil;

10% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and,

q.s. water 100%.

Formulation XIV

0.1% w/v latanoprost;

5.0% w/v minoxidil or minoxidil sulphate;

20% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and,

q.s. water 100%.

Formulation XV

0.1% w/v latanoprost;

2.0% w/v minoxidil or minoxidil sulphate;

20% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and,

q.s. water 100%.

Formulation XVI

0.1% w/v bimatoprost;

5.0% w/v minoxidil;

20% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and,

q.s. water 100%.

Formulation XVII

0.1% w/v travoprost;

5.0% w/v minoxidil;

20% w/v 2-(2-Ethoxyethoxy)-Ethanol;

5% w/v propanediol;

3% w/v oleic acid; and,

q.s. water 100%.

Formulation XVIII

0.1% w/v latanoprost;

5.0% w/v minoxidil;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XVIIII

0.1% w/v latanoprost;

5.0% w/v minoxidil;

30.0% w/v ethanol;

50% w/v propylene glycol;

3% w/v diethylene glycol monoethyl ether;

2% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation XX

0.3% w/v latanoprost;

5.0% w/v minoxidil;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXI

5.0% w/v minoxidil or minoxidil sulphate;

0.05% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXII

5.0% w/v minoxidil;

0.05% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXIII

5.0% w/v minoxidil;

0.008% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol;

q.s. water.

Formulation XXIV

5.0% w/v minoxidil;

0.007% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXV

5.0% w/v minoxidil;

0.005% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXVI

3.0% w/v finasteride;

0.1% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%

Formulation XXVII

5.0% w/v finasteride;

0.3% w/v latanoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXVIII

5.0% w/v finasteride;

0.3% w/v bimatoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXVIIII

5.0% w/v finasteride;

0.1% w/v bimatoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXX

5.0% w/v finasteride;

0.1% w/v travoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXXI

5.0% w/v finasteride;

0.3% w/v travoprost;

30.0% w/v ethanol;

50% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXXII

0.1% w/v latanoprost;

47% w/v ethanol;

0.4% w/v polysorbate 60;

1% w/v polyethylene lauryl alcohol;

0.3% w/v acetic acid;

10% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXXIII

0.3% w/v latanoprost;

47% w/v ethanol;

0.4% w/v polysorbate 60;

1% w/v polyethylene lauryl alcohol;

0.3% w/v acetic acid;

10% w/v propylene glycol; and,

q.s. water 100%.

Formulation XXXIV

0.08% w/v latanoprost;

4.0% w/v minoxidil;

50% w/v propylene glycol;

30% w/v ethanol;

3% w/v transcutol;

2% w/v oleyl alcohol;

0.5% w/v POE 40; and,

q.s. water 100%.

Formulation XXXV

0.08% w/v latanoprost;

4.0% w/v minoxidil;

50% w/v propylene glycol;

30% w/v ethanol;

3% w/v transcutol;

2% w/v oleyl alcohol; and,

q.s. water 100%.

Formulation XXXVI

0.1% w/v latanoprost;

47% w/v ethanol;

0.4% w/v polysorbate 60;

1% w/v polyethylene lauryl alcohol;

0.3% w/v acetic acid;

2.0% w/v oleic acid;

10% w/v propylene glycol; and,

q.s. water 100%.

Non-Aerosol. Non-Spray Foam Pump and Container

In another embodiment, a final product of a liquid formulationcomprising the active ingredient combination of bimatoprost/minoxidil ortravoprost/minoxidil or latanoprost/minoxidil or bimatoprost/finasterideor travoprost/finasteride or latanoprost/finasteride or apharmaceutically acceptable salt thereof, packaged in a non-pressurizedcontainer, is dispensed using a non-aerosol, non-spray foam pump. Thenon-aerosol, non-spray foam pump provides for safe and simple dispensingof a measured dosage of the foam that contains the liquid formulationcomprising the drug combination or a salt thereof, that is readilyapplied to the scalp, eyebrows, eyelashes or face. The non-aerosol,non-spray foam pump is calibrated to deliver an adequate volume of thefoam. An additional object herein disclosed is to provide the liquidformulation in a reusable and non-pressurized container that can bemanufactured in a cylindrical or non-cylindrical shapes and thatcontains no propellant. Therefore, the present embodiment does notemploy the use of pressurized containers containing typical propellants,such as liquefied petroleum gases (mixture of propane, isobutene, andn-butane), chlorofluorocarbons (CFCs), and dimethyl ether, which areflammable, harmful, and toxic volatile organic compounds (VOCs). Thepresent embodiment is safely transported, stored, and dispensed inreusable containers. Reusing products and the parts of products isextremely important for the environment.

Foam Formulations

Foam formulations comprising the active ingredient combination ofbimatoprost/minoxidil or travoprost/minoxidil or latanoprost/minoxidilor bimatoprost/finasteride or travoprost/finasteride orlatanoprost/finasteride or a pharmaceutically acceptable salt thereof.Preferably the amount of surfactant is about 2-10%. Any combination ofanionic, cationic, non-ionic or amphoteric surfactants and non-ionicblock copolymers may be used. Preferably ethoxylated glycerides,ethoxylated sorbitan esters, polyethoxylated and/or hydrogenated castoroil, nonionic block copolymers and amphoteric surfactants may be used.Especially preferred surfactants may be selected from: PEG 40hydrogenated castor oil; PEG 40 Stearate; Polysorbate 20; Cocamidopropylbetaine; Glyceryl cocoate; PEG 6 caprylic/capric glycerides; Poloxamer F68; and saturated phospholipids C6 to C10.

Formulation XXXVII (Spray Solution)

Minoxidil 5.0% w/v (active);

Latanoprost 0.1% w/v or 0.3% w/v (active);

1,2-Propanediol 60.5% w/v (solvent);

Ethyl alcohol 10.2% w/v (solvent);

lactic acid 2.5% w/v (acidifying agent);

Essence 0.06% w/v (aroma/essence); and

deionized water q.s. 100% (solvent).

The production flow scheme for formulation XXXVI I is as follows: 1:Minoxidil, latanoprost and other excipients are separately weighed andprepared; 2: 1,2-propanediol, lactic acid, ethyl alcohol and deionizedwater which have been respectively weighed are placed in a productionvessel and are mixed for at least 5 minutes, 3: The previously weighedminoxidil is placed in a stainless steel production vessel and is mixedfor at least 15 minutes in order to be dissolved, followed by theaddition of the previously weighed latanoprost (in a preweighed syringeto ensure proper transfer of the oil)4: Essence is added and mixed; 5:Filling is carried out at target volume and the end product is packagedand boxed.Formulation XXXVIII; Minoxidil 2/latanoprost 0.1 SprayMinoxidil 2% w/v (active);Latanoprost 0.1% w/v or 0.3% w/v (active);1,2-Propanediol 65.9% w/v (solvent/excipient);Ethyl Alcohol 5.2% w/v (solvent);Lactic Acid 2.5% w/v (acidifying agent);Essence 0.06% w/v (aroma/essence); and,Deionized water q.s. (solvent).The production flow scheme of the formulation is the same as FormulationXXXVII.Formulation XXXIX: minoxidil 5/latanoprost 0.1 or 0.3 FoamMinoxidil 5.0% w/v (active);Latanoprost 0.1% w/v or 0.3% w/v (active);1,2-Propanediol 51.5% w/v (solvent/excipient);PEG 20 Oleyl Ether 0.5% w/v (surface active agent);Plantacare 1200*10.5% w/v (surface active agent);Komperlan KD**3% w/v (surface active agent);Ethyl alcohol 5.2% w/v (solvent) (EP);Lactic Acid 2.4% w/v (acidifying agent) (EP);Essence 0.06% w/v (Aroma/Essence [EP]); and,Deionized water 21.8% Solvent (EP).*Lauryl glycoside**Cocamide DEA=Coconut fatty Acid DiethanolamineThe production flow scheme of the formulation is as follows:minoxidil, latanoprost and other excipients are separately weighed andprepared, 1,2-propanediol, lactic acid, ethyl alcohol and deionizedwater which have been respectively weighed are placed in a productionvessel and are mixed for at least 5 minutes, the previously weighedminoxidil is placed in a stainless steel production vessel and is mixedfor at least 15 minutes in order to be dissolved, followed by theaddition of the previously weighed latanoprost. The previously weighedPEG 20 oleyl ether, plantacare 1200 and komperlan KD is added in astainless steel production vessel and dissolved, essence is added andmixed. Filling is carried out at target volume and the end product ispackaged and boxed.Formulation XXXX: minoxidil 2.0%/latanoprost 0.1% FoamMinoxidil 2% w/v;Latanoprost 0.1% w/v or 0.3% w/v;1,2-Propanediol 51.% w/v (solvent/excipient);PEG 20 Oleyl Ether 0.5% w/v (surface active agent);Plantacare 1200 10.5% w/v (surface active agent);Komperlan KD 3% w/v (surface active agent);Ethyl Alcohol 5.2% w/v (solvent);Lactic Acid 2.4% w/v (acidifying agent);Essence 0.06% w/v 9 w/v (Aroma/Essence); and,q.s. deionized water.Formulation XXXXI (Lotion)Minoxidil 5% w/v;Latanoprost 0.1% or 0.3% w/v;Ethanol 60.3% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylene lauryl alcohol 1.00% w/v;Acetic Acid 0.6% w/v; and,Purified Water to total 100%.The apparent pH of the final formulated solution should be 6.24.Formulation XXXXIIMinoxidil 5% w/v;Latanoprost 0.1% or 0.3% w/v;Cetyl Alcohol 2.20% % w/v;Stearyl Alcohol 1.00% w/v;Ethanol 51.8% w/v;Polysorbate 60 0.4% % w/v;Polyoxyethylene lauryl alcohol 1.00% % w/v;Propylene Glycol 5.00% % w/v;Propellant P75 4.30% % w/v;Acetic Acid q.s. pH 6.0; and,Purified water to total 100%.Formulation XXXXIII (Lotion)Minoxidil 8% w/v;Latanoprost 0.3% or 0.1% w/v;Ethanol 50.5% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylene lauryl alcohol 1.00% w/v;Acetic Acid q.s. pH 6.0;Propylene Glycol 7.3% w/v;Benzyl Alcohol 5% w/v; and,Purified Water to total 100%.Formulation XXXXIV (Solution)Latanoprost 0.1%, 0.2%, or 0.3% w/v;Minoxidil 5% w/v;Ethanol 51% w/v;Polysorbate 60 0.4% w/v;Laureth-12 1% w/v;Glacial Acetic Acid 0.3% w/v;Propylene Glycol 7.5% w/v;Benzyl Alcohol 5% w/v; and,Purified Water to total 100%.pH of about 6.24.Formulation XXXXVMinoxidil 8% w/v;Latanoprost 0.3% or 0.1% w/v;Ethanol 50.0% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylene lauryl alcohol 1% w/v;Acetic Acid q.s. pH 6.0 w/v;Propylene Glycol 10% w/v;Benzyl Alcohol 5% w/v; and,Purified Water to total 100%Formulation XXXXVI (Lotion)Minoxidil 5% w/v;Latanoprost 0.1% or 0.3% w/v;Ethanol 47.50% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylene lauryl alcohol 1.00% w/v;Acetic Acid q.s. pH 6.0;Benzyl Alcohol 5% w/v; and,Purified Water to total 100%.Formulation XXXXVIIMinoxidil 5% w/v;Latanoprost 0.1% w/v;Ethanol 47% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylenelauryl alcohol 1% w/v;Acetic Acid 1% w/v;Propylene Glycol 10% w/v;Benzyl Alcohol 5% w/v; and,Purified Water QS 100%.Formulation XXXXVIIIMinoxidil 5% w/v;Latanoprost 0.3% w/v;Ethanol 44.2% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylenelauryl alcohol w/v 1% w/v;Acetic Acid 0.3% w/v;Propylene Glycol 30% w/v;Benzyl Alcohol 2% w/v; and,Purified Water QS 100%.Formulation XXXXIXMinoxidil 5% w/v;Latanoprost 0.3% w/v;Ethanol 46% w/v;Polysorbate 60 0.4% w/v;Polyoxyethylenelauryl alcohol 1% w/v;Acetic Acid 0.3% w/v;Propylene Glycol 30% w/v;Benzyl Alcohol 10% w/v; and,Purified Water QS 100%.Formulation XXXXXMinoxidil sulphate 4% w/v;Latanoprost 0.08% w/v;Ethanol 30% w/v;Propylene Glycol 50% w/v;Oleyl Alcohol 2% w/v;Transcutol 3% and,Purified Water QS 100%.

The apparent pH of the final Formulations XXXXIV-XXXXX adjusted to6.0-6.5 benzyl alcohol can be eliminated for single use formulations andsubstituted with propylene glycol.

OTHER EMBODIMENTS

Other formulations include a composition comprising up to 5% w/wminoxidil, latanoprost at about 0.1% w/w; carbomer at about 0.15% w/w;triethylamine (TEA) at about 0.22% w/w; ethanol at about 15.0% w/w;diethylene glycol monoethyl ether at about 10.0% w/w; polysorbate 20 atabout 4.0% w/w; and water at about 70.5% w/w.

A composition comprising up to 5% w/w minoxidil, latanoprost at about0.1% w/w; carbomer at about 0.10% w/w; NaOH at about 0.035% w/w; ethanolat about 15.0% w/w; diethylene glycol monoethyl ether at about 10.0%w/w; and water at about 74.8% w/w.

A composition comprising up to 5% w/w minoxidil, latanoprost at about0.1% w/w; carbomer at about 0.125% w/w; TEA at about 0.18% w/w; ethanolat about 30.0% w/w; diethylene glycol monoethyl ether at about 20.0%w/w; and water at about 49.59% w/w.

A composition comprising up to 5% w/w minoxidil, latanoprost at about0.1% w/w; carbomer at about 0.10% w/w; TEA at about 0.15% w/w; ethanolat about 30.0% w/w; propylene glycol at about 20% w/w; and water atabout 49.7% w/w.

A composition comprising up to 5% w/w minoxidil, latanoprost at about0.1% w/w; carbomer at about 0.20% w/w; TEA at about 0.22% w/w; ethanolat about 60.0% w/w; glycerin at about 5.0% w/w; and water at about34.48% w/w.

A composition comprising up to 5% w/w minoxidil, latanoprost at about0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w; ethanolat about 60.0% w/w; polysorbate 20 at about 4.0% w/w; and water at about35.27% w/w.

A composition or solution comprising 4% w/v minoxidil, 0.08% w/vlatanoprost, 50% w/v propylene glycol, 30% w/v ethanol, 3% w/vtranscutol, 2% w/v oleyl alcohol, 0.5% w/v Polyoxyethylene 40, and q.s.water 100%.

A composition or solution comprising 4% w/v minoxidil, 0.08% w/vlatanoprost, 50% w/v propylene glycol, 30% w/v ethanol, 3% w/vtranscutol, 2% w/v oleyl alcohol, and q.s. water 100%.

A composition comprising up to 5% w/w minoxidil, latanoprost at about0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w; ethanolat about 50.0% w/w; diethylene glycol monoethyl ether at about 10% w/w;polysorbate 20 at about 4.0% w/w; and water at about 35.27% w/w.

It is extremely challenging to formulate two insoluble drugs such asminoxidil and latanoprost together into a single aqueous composition.Both compounds have poor solubility in water and require highconcentrations of solvents and or cosolvents to keep both compounds insolution particularly at the very high concentrations of minoxidil whichis often 2-7% w/v. Further, it is noted that many consumers find thegeneric Rogaine® formulation unpleasant or intolerable in that it issticky and many users perceive that it leaves a sticky or greasy residuewhich decreases patient compliance. This is believed to be mainly due topropylene glycol which is present at 50% w/v which is necessary tosolubilize the high concentration of minoxidil, generally at 5% w/v,which is a very insoluble substance. It has been found that addition oflow concentrations diethylene glycol monoethyl ether and oleyl alcoholmade the solution less sticky and more pleasant to the touch and feel ofthe solution. It was also surprisingly found that not only did theaddition of these compounds result in a better feeling formulation, theaddition of these compounds, particular diethylene glycol monoethylether and oleyl alcohol in low concentrations, resulted in a moreefficacious formulation that was superior in growing hair. Although notwishing to be bound to any theory, it is believed that the combinationof diethylene glycol monoethyl ether and oleyl alcohol actsynergistically at certain concentrations, increase skin penetration ofthe active agents (e.g., latanoprost and minoxidil) and fluidize thelipids of hair follicle and the stratum corneum and make both activeagents more soluble in vivo which make the formulations more efficaciousby increasing the bioavailability of the active agents. Latanoprost ismostly lipid soluble which allows it to penetrate into the hairfollicles of the epidermis. However, when used in combination withcertain solvents such as diethylene glycol monoethyl ether and oleylalcohol, the formulation becomes more effective in exfoliating the porelining, loosens clogs, removes impurities, and allows the formulation topermeate more freely. By weakening the cellular glue, so to speak,exfoliation opens up the hair follicle and pores. This would account forthe increased efficacy of these formulations as compared to the sameformulations that did contain diethylene glycol monoethyl ether andoleyl alcohol.

In some embodiments, the composition comprises water, minoxidil,latanoprost at a concentration of about 0.01% w/w to about 0.4% w/w, orabout 0.05-0.3% w/w, or about 0.1-0.3% w/w. Minoxidil is comprised in anamount of about 0.5-10% w/w, or about 1-6% w/w, or about 2-5% w/w orabout 5% w/w and one or more selected from the group consisting of:cetostearyl alcohol at a concentration of about 0.5% w/w to about 1%w/w, glyceryl mono-oleate at a concentration of about 1% w/w to about 3%w/w, preferably about 2% w/w, oleyl alcohol at a concentration of about1% w/w to about 3% w/w, preferably about 2% w/w, ethanol at aconcentration of about 30% w/w to about 75% w/w, propylene glycol at aconcentration of about 10% w/w to about 25% w/w, benzyl alcohol at aconcentration of about 0.5% w/w to about 2% w/w, preferably about 1%w/w, carbomer at a concentration of about 0.15% w/w, triethanolamine ata concentration of about 0.16% w/w, and glycerol at a concentration ofabout 0.5% w/w to about 10% w/w, preferably 2% w/w.

In some embodiments, the composition comprises water, minoxidil,latanoprost at a concentration of about 0.01-0.5% w/w, or about 0.05-4%w/w, or about 0.1-0.5% w/w. Minoxidil is comprised in an amount of about0.5-10% w/w, or about 1-6% w/w, more or about 2-5% w/w or about 5% w/wand one or more selected from the group consisting of transcutol at aconcentration of about 1% w/w to about 25% w/w, preferably about 10%w/w, propylene glycol at a concentration of about 1% w/w to about 25%w/w, glycerol monooleate at a concentration of about 1% w/w to about 3%w/w, preferably about 2% w/w, oleyl alcohol at a concentration of about1% w/w to about 3% w/w, preferably about 2% w/w, ethanol at aconcentration of about 30% w/w to about 75% w/w, propylene glycol at aconcentration of about 10% w/w to about 25% w/w, benzyl alcohol at aconcentration of about 0.5% w/w to about 2% w/w, preferably about 1%w/w, carbomer at a concentration of about 0.15% w/w to about 0.2% w/w,triethanolamine at a concentration of about 0.16% w/w, and glycerin at aconcentration of about 0.5% w/w to about 10% w/w, preferably 2% w/w.

Some embodiments may also comprise one or more additional ingredients inaddition to those specified in the paragraph above, wherein the one ormore ingredients are selected from the group consisting of linoleic acidat a concentration of about 1% w/w to about 5% w/w, preferably 2% w/w,sodium lauryl sulfate at a concentration between 0.1% w/w to about 0.5%w/w, preferably 0.2% w/w, and docusate sodium at a concentration between0.1% w/w to about 0.5% w/w, preferably 0.2% w/w.

In some embodiments, the composition comprises water, minoxidil,latanoprost or travoprost at a concentration of about 0.01-5% w/w, orabout 0.05-4% w/w, or about 0.1-0.3% w/w or about 0.1% w/w, 0.2% w/w or0.3% w/w. Minoxidil is comprised in an amount of about 0.5-10% w/w, orabout 1-6% w/w, or about 2-5% w/w or about 5% w/w and one or moreselected from the group consisting of: transcutol at a concentration ofabout 1% w/w to about 25% w/w, preferably about 10% w/w, propyleneglycol at a concentration of about 1% w/w to about 25% w/w, glycerolmonooleate at a concentration of about 1% w/w to about 3% w/w,preferably about 2% w/w, oleic acid at a concentration of about 1% w/wto about 3% w/w, preferably about 2% w/w, linoleic acid at aconcentration of about 1% w/w to about 3% w/w, preferably about 2% w/w,ethanol at a concentration of about 30% w/w to about 75% w/w, propyleneglycol at a concentration of about 10% w/w to about 25% w/w, benzylalcohol at a concentration of about 0.5% w/w to about 2% w/w, preferablyabout 1% w/w, carbomer at a concentration of about 0.15% w/w to about0.2% w/w, triethanolamine at a concentration of about 0.16% w/w,glycerin at a concentration of about 0.5% w/w to about 10% w/w,preferably about 2% w/w, essential oil at a concentration of about 0.05%w/w to about 5% w/w, preferably about 1% w/w, limonene at aconcentration of about 0.5% w/w to about 5% w/w, preferably about 1%w/w, nerol at a concentration of about 0.5% w/w to about 5% w/w,preferably about 1% w/w, cineol at a concentration of about 0.5% w/w toabout 5% w/w, preferably about 1% w/w, octyl salicylate at aconcentration of about 0.5% w/w to about 5% w/w, preferably about 2%w/w, DMSO at a concentration of about 0.5% w/w to about 5% w/w,preferably about 2% w/w, DDAB at a concentration of about 0.01% w/w toabout 1% w/w, preferably about 0.2% w/w, sodium taurodeoxycholate at aconcentration of about 0.01% w/w to about 5% w/w, preferably about 2%w/w, docusate sodium at a concentration of about 0.01% w/w to about 1%w/w, preferably about 0.2% w/w, myristyl myristate at a concentration ofabout 1% w/w to about 30% w/w, preferably about 25% w/w, polysorbate 80at a concentration of about 1% w/w to about 5% w/w, preferably about 2%w/w, silicone elastomer in cyclomethicone at a concentration of about40% w/w to about 80% w/w, preferably about 73.5% w/w, Dow Silky Wax 10at a concentration of about 1% w/w to about 20% w/w, preferably about 8%w/w, isopropyl myristate at a concentration of about 1% w/w to about 20%w/w, preferably about 8% w/w.

In some embodiments, the composition comprises water; minoxidil orfinasteride, latanoprost or travoprost, for example with latanoprost ortopical finasteride at a concentration from about 0.01% w/w to about0.5% w/w, preferably about 0.05-0.45% w/w or about 0.075-0.4% w/w, morepreferably about 0.1-0.3% w/w the most preferred value being 0.1% w/w,0.2% w/w or 0.3% w/w. Minoxidil or finasteride comprised in an amount ofabout 0.5-10% w/w, or about 1-6% w/w, or about 2-5% w/w or about 5% w/w;and one or more selected from the following: ethanol, for example at aconcentration between 0.01% w/w to about 89% w/w; propylene glycol, forexample at a concentration between 0.01% w/w to about 89% w/w;diethylene glycol monoethyl ether, for example at a concentrationbetween 0.01% w/w to about 89% w/w; benzyl alcohol, for example at aconcentration between 0.01% w/w to about 89% w/w; and one or more fattyacids and/or fatty ester excipients, for example at a concentrationbetween 0.01% w/w to about 10% w/w. In some embodiments, the fatty acidsmay include one or more C8-mC28 fatty acids, and which may be saturated,monounsaturated, or polyunsaturated. In some embodiments, a saturatedfatty acid may be stearic acid. In some embodiments, a monounsaturatedfatty acid may be oleic acid. In some embodiments, a polyunsaturatedfatty acid may be linoleic acid. In some embodiments, the fatty estermay one or more include C8-C28 fatty acids, and which may be saturated,monounsaturated, or polyunsaturated. In some embodiments, a saturatedfatty ester may be glyceryl monostearate. In some embodiments, amonounsaturated fatty ester may be glyceryl monooleate. In someembodiments, a polyunsaturated fatty ester may be ethyl ester oflinoleic acid.

A preferred composition comprises minoxidil or finasteride, latanoprostor travoprost, oleyl alcohol, ethanol and propylene glycol. Latanoprostor travoprost is comprised in an amount of about 0.01-0.5% w/w, or about0.05-0.4% w/w, or about 0.1-0.3% w/w the most preferred or about 0.1%w/w, 0.2% w/w or 0.3% w/w. Minoxidil or finasteride is comprised in anamount of about 0.5-10% w/w, or about 1-6% w/w, or about 2-5% w/w orabout 5% w/w. Oleyl alcohol is comprised in an amount of about 1-10%w/w. Ethanol is comprised in an amount of about 50-80% w/w. Propyleneglycol is comprised in an amount of 15-15% w/w.

Examples of particularly preferred compositions for growing hair bytopical application comprise minoxidil or finasteride, latanoprost ortravoprost in free form or a pharmaceutically acceptable salt thereof,wherein the latanoprost or travoprost is contained in an amount of about0.1% w/w to about 4% w/w; minoxidil or finasteride is comprised in anamount of about 0.5-10% w/w, preferably about 1-6% w/w, more preferablyabout 2-5% w/w the most preferred value being 5% w/w.; at least onefirst compound selected from a fatty acid, fatty acid alcohol and fattyester, wherein said composition is formulated for topical administrationto the skin.

In some embodiments, the first compound is a fatty acid. The fatty acidmay be saturated or unsaturated. In some embodiments, the fatty acid isselected from the group consisting of stearic acid, oleic acid, linoleicacid, and mixtures thereof. In some embodiments, the first compound is afatty ester. The fatty ester may be saturated or unsaturated. The fattyester may be selected from the group consisting of glycerylmonostearate, glyceryl monooleate, and ethyl ester of linoleic acid. Insome embodiments, the composition comprises at least two firstcompounds. The composition may comprise a mixture of at least one fattyacid and at least one fatty ester. The first compound may have 12-24carbon atoms. The composition may further comprise at least one secondcompound selected from the group consisting of ethanol, propyleneglycol, diethylene glycol monoethyl ether, and benzyl alcohol. Thecomposition may further comprise at least one third compound selectedfrom the group consisting of terpenes, occlusive agents, surface activeagents, sulfoxides, cyclic ethers, amides, amines, anddimethylaminopropionic acid derivatives. In some embodiments, theterpene is selected from the group consisting of terpinolene, limonene,nerol, and cineol. In some embodiments, the occlusive agent is selectedfrom the group consisting of silicones, mineral oils, and waterinsoluble polymers. In some embodiments, the surface active agent isselected from the group consisting of polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, sodium dodecyl sulfate, sodium laurylsulfate, DMSO, and docusate sodium. In some embodiments, thedimethylaminopropionic acid derivative is 2-dimethylaminopropionic aciddodecyl ester. The composition may comprise latanoprost in an amount ofabout 0.01% w/w to about 4% w/w. More preferably, the composition maycomprise latanoprost in an amount of about 0.05% w/w to about 0.5% w/w.Most preferably, the composition may comprise latanoprost in an amountof about 0.1% w/w. In some embodiments minoxidil is comprised in anamount of about 0.5-10% w/w, preferably about 1-6% w/w, more preferablyabout 2-5% w/w the most preferred value being 5% w/w. the composition isin the form of one selected from the group consisting of solutions,gels, ointments, foams, films, liniments, creams, shampoos, lotions,pastes, jellies, sprays and aerosols. In some embodiments, thecomposition is packaged in a kit with an applicator for application tothe skin.

The compositions and formulations of the present invention can bemanufactured using the following general procedure:

Non-aqueous components (e.g. latanoprost, travoprost, minoxidil,finasteride ethanol, glycols) are combined in a beaker and stirred usinga propeller type overhead mixer until the solution is clear. Water isadded to the non-aqueous mixture followed by the addition of thethickening agent. Upon dispersion of the thickening agent, a base isadded to neutralize the polymer and thicken the solution into a gelother desired composition. For example, ethanol, minoxidil andlatanoprost are combined in a beaker and stirred using a propeller typeoverhead mixer until the solution is clear. This mixture is then addedto the non-aqueous ingredients to form a non-aqueous mixture. In aseparate vessel the thickening agent is dispersed in water to form anaqueous mixture, which is then added to the non-aqueous mixture. Uponmixing of the non-aqueous and aqueous mixtures, a base is added toneutralize the polymer and to thicken the solution into a gel.

The compositions of the present invention can be manufactured using thefollowing general procedure:

Ethyl alcohol is weighed into a suitable media jar equipped for mixing,bimatoprost, latanoprost or travoprost is then added to the ethylalcohol and stirred at moderate speed until dissolved. Into separatemixing tank, minoxidil, diethylene glycol monoethyl ether, oleylalcohol, propylene glycol and optionally POE 40 are added and mixeduntil the solvents are dispersed. Ethyl alcohol/(bimatoprost,latanoprost, or travoprost) solution is then added into the non-aqueoussolution and mixed until the components are homogenously mixed (about 5minutes of mixing). If a gel is desired, to the above mixture thecarbomer thickener previously dispersed in water is added and mixeduntil well dispersed, once dispersed a base is added to thicken thesolution into a gel.

A topical 0.0.5% w/w latanoprost/5% w/w minoxidil cream is prepared asfollows: Medium viscosity carboxymethyl cellulose and spermaceti aremelted together at a temperature of 70-80° C. Propylene glycol,polysorbate 80, latanoprost, minoxidil and transcutol are added in turn,maintaining a temperature of 75-80° C. A preservative (e.g.,methylparaben) is added slowly to the carboxymethyl cellulose andspermaceti melt, with constant stirring. The addition is continued forat least 30 minutes with additional stirring until the temperature hasdropped to 40-45° C. Finally, sufficient water is added to bring thefinal weight to 1000 gm and the preparation stirred to maintainhomogeneity until cooled and congealed.

Once formulated, the formulations may be applied continuously daily,monthly or yearly.

Example I

A 42-year old Caucasian man with alopecia areata applies the formulationof Formulation VIII twice a day, 2 ml/day to areas on his scalp wherehair loss is evident, presenting as small patches of hair lossapproximately the size of a quarter. After thirty days of application,there will be fewer T cell infiltrates in the patient's scalp hairfollicles and the patient's hair will begin to grow on the patches.

Example II

A 32-year old male with androgenetic alopecia applies the formulation ofFormula VI to areas of hair loss on his scalp at least once a day (1ml/day). After forty-five days of continuous application, the underlyingautoimmune response causing hair loss will lessen in severity and hairwill begin to regrow on the patient's scalp in the areas of hair loss.

Example III

A 43-year old female suffering from telogen effluvium applies theformulation of Formula XVII to her scalp twice a day. After thirty-fivedays of daily application, the patient's hair will begin to regrow onthe patient's scalp in areas where the patient suffered hair loss. Thepatient will experience no side effects from application of FormulationXVII to the scalp.

Example IV

A 62 year old woman with thinning eyebrows applies Formulation XXII toher eyebrows with an applicator once a day. Within 45-90 days, thepatient will experience increased growth of eyebrow hairs which arelonger, thicker and darker than eyebrow hairs had she not have appliedFormulation XXII.

Example V

A 53-year old male shaved an approximately one inch by one inch area theunderside of his left and right forearm. All hair above the epidermiswas removed. The patient applied approximately 0.5 ml of Formulation XIonce each day to the left forearm but left the right forearm untreated.After 20 days, the hairs on the left forearm were more numerous, longer,darker and thicker as compared to the hairs on the right forearm whichwere less numerous, shorter, lighter and not as thick. After 30 days,the hairs on the left forearm were more numerous, longer, darker andthicker as compared to the hairs on the right forearm which were lessnumerous, shorter, lighter and not as thick. The patient experienced noside effects.

Example VI

A 53-year old male shaved a four inch by two-inch area above his leftand right knee to remove all hair above the epidermis and applied theformulation of Formula XI to the shaved area above the left knee once aday and 5% minoxidil generic ROGAINE® solution above the right knee oncea day. After twenty days the hair growth in the area shaved above theleft knee is slightly greater (more hair, longer hair and thicker) thanin the area shaved above the right knee. After 30 days the hair in thearea above the left knee is longer, darker and thicker than the areaabove the right knee. After 45 days, the hair above the left knee issignificantly longer, thicker in diameter, darker and more numerous thanthe area above the left knee which was treated with a 5% minoxidilRogaine® solution. The patient suffered no side effects.

Example VII

A 54 year old Caucasian male shaved three one-inch-by-one inch squareareas (Areas #1-#3) on his thigh, two side by side and one below. Allhair above the epidermis was removed. Areas #1 and #2 were treated andArea #3 received no formulation and served as a control. The patientapplied about one-third ml of Formulation XX per day to Area #1 andone-third milliliter of Formulation XVIII to Area #2. Area #3 receivedno treatment and served as a control. After 30 days, both Areas 1 and 2had significant hair growth, the hairs were longer, darker and thickeras compared to the control (Area #3). There did not appear to be asignificant difference between Area #1 and Area #2 in regard to lengthof hair or darkness or thickness after 30 days. However, Area #1 andArea #2 had significantly more hair growth than Area #3. After 60 days,both Areas #1 and #2 had significant hair growth but the differencebetween the two areas in regard to length, thickness and darkness wasnot significant with Area #1 having about 10% more and longer hair thanArea #2.

In regard to darkness and thickness, there appeared to be no significantdifference between Areas #1 and #2.

Example VIII

A Caucasian male, age 53, with balding on his crown roughlycorresponding to stage IV on the Hamilton Norwood Scale, appliedFormulation XX once a day, at approximately 1 ml/day to his crown andthe front of his head. At Day 75, the patient switched to FormulationXVIII. After 90 days, the patient experienced significant regrowth tohis crown with approximately 40-50% of the balding area being reduced inarea with new hair growth (see FIG. 5). Most of the new hair growth waswith darker hair of the patient's natural hair color and the overallratio of dark hair to grey hair increased significantly in the treatedarea. The new hair was longer, darker and thicker as compared to thevellus hair in the balding area of his crown. The patient alsoexperienced significant regrowth in the front of his head whereformulation was applied. The patient experienced no side effects.

Example IX

A 54 year old male shaved three areas of his thigh above his knee inapproximately two inch by three inch areas where the hair was closelyshaved down to the surface of the epidermis. Two areas on the left thighseparated by several inches in distance and an area on his right thigh.The subject applied no formulation to Area #1 and left that areauntreated, applied a generic 5% minoxidil Rogaine® solution to Area #2at approximately 0.3 ml/day, and applied a minoxidil/latanoprostformulation (Formulation XVIII) to Area #3 at approximately 0.3 ml/day.After approximately 15 days, the untreated area showed some hair growthwhile Area #2 and Area #3 experienced more pronounced hair growth ascompared to Area #1. Area #2 and Area #3 were very similar in numbersand lengths of hairs but the hairs of Area #3 appeared slightly darkerand thicker. At Day 30, all three areas experienced regrowth with Areas#2 and #3 having significantly greater numbers of hair, which werelonger, darker and with greater diameter as compared to Area #1. At Day30, the number of hairs in Areas #2 and #3 were roughly the same but thehairs of Area #3 appeared slightly darker and thicker than Area #2. AtDay 45, Area 1 had regrowth, approximately half of the hairs wereregrown but was significantly less than Areas #2 and #3. At Day 45, Area#3 had significantly more hairs than Area #2, with greater length,darkness and thickness as compared to Area #2.

Example X

A 54 year old male patient shaved three areas (approximately one inch byone inch) on his thigh so all of the hair was removed from those areasabove the dermis. Once a day, the patient begins applying FormulationXXXV on Area #1, then an identical formulation but without latanoprost(4% w/v minoxidil solution) to Area #2, and an identical formulation toFormulation XXXV but without minoxidil (0.08% w/v latanoprost solution)to Area #3. After fifteen days, Area #1 had earlier onset of hair growthand experienced greater regrowth and an earlier onset of hair ascompared to areas #2 and #3 in that there were more hairs growing abovethe epidermis, with greater thickness and greater darkness than areas #2and #3. There was little to no difference between the hair growth interms of numbers of hair, length of hair, thickness of hair or darknessof hair between areas #2 and #3 on Day 15. By Day 30, area #1 had moreregrowth as compared to areas #2 and #3 with more hair, longer hairs,thicker hairs and darker hairs compared to area #3. Area #1 had aquicker onset of hair growth and greater hair growth as compared toareas #2 and #3. The patient experienced no side effects.

Example XI

A Caucasian female, age 46, with balding and thinning hair along hervertex corresponding to stage I on the Ludwig scale, applied FormulationXX on her head along her vertex twice a day with about 2 ml/day beingapplied for approximately 30 days. At approximately Day 31, the patientbegan to apply Formulation XVI once a day (1 ml/day) to her head alongher vertex. By Day 45, the patient's vertex had filled in significantlywith new hair growth that was of her original hair color wherein theratio of dark hair to grey hair increased considerably with more darkhair of her original hair color as compared to grey hair (see FIG. 4).The individual hairs of the new hair growth were also thicker ascompared to her existing hairs. The patient experienced no side effects.

Example XII

A 54 year old patient shaved three areas (approximately one inch by oneinch) on his arm so all of the hair was removed from above the surfaceof the epidermis. Once a day, the patient applied Formulation XVIII onarea #1, an identical solution to Formulation XVIII but without thelatanoprost on area #2 and an identical solution to Formulation XVIIIbut without the minoxidil on area #3. After fifteen days, area #1 hadearlier onset of hair growth and more hair growth (more hair growingabove the epidermis, longer, darker and thicker) than areas #2 and area#3. By Day 30, the trend continued with area #1 experiencing significantregrowth as compared to area #2 and area #3. By Day 45, the area #1 hadalmost completely grown back as compared to either area #2 or area #3.Area #3 had slightly darker and thicker hair as compared to area #2 butarea #2 growth was slightly longer than area #3. However, area #1 hadmore growth with longer, darker and thicker hair than area #3 and longerhair than area #2.

Example XIII

A 54 year old patient removed hair by shaving three areas (approximately1 inch by one inch) on his upper thigh so all of the hair was removedfrom these areas. Once a day, the patient applied Formulation XVIII onArea #1, Formulation XXXV on area #2 and no formulation on Area #3.After fifteen days, both Area #1 and Area #2 experienced significantregrowth as compared to area #3. The hairs in Areas #1 and #2 werelonger, darker, thicker and more numerous as compared to Area #3. By Day30, both Areas #1 and #2 had significant regrowth as compared to Area #3with more hair, longer hairs, thicker hairs and darker hairs compared toarea #3. By Day 45, the Areas #1 and #2 were both almost completelygrown back and area #3 had significantly less hair growth than eitherAreas #1 or #2.

There was no significant difference in hair growth between Areas #1 and#2. The patient experienced no side effects.

Example XIV

A 54 year old patient removed hair by shaving three areas (approximately1 inch by one inch), two on his right calf and one on his left calf soall of the hair was removed above the epidermis in these areas. Once aday, the patient applied Formulation XVIII on Area #1, an area on hisleft calf, no formulation on Area #2 on his less calf and FormulationXIX on Area #3. After fifteen days, both Area #1 and Area #3 experiencedsignificant regrowth as compared to Area #2 with Area #3 having morehair growth (more hair, longer, and thicker) than Area #2. By Day 30,both Areas #1 and #3 had significant regrowth as compared to Area #2with more hair, longer hairs, thicker hairs and darker hairs compared toArea #3. By Day 30, Area #3 had significantly more hair growth with morenumerous, longer, and darker hair than Area #2 by approximately 20%. Thepatient experienced no side effects.

Example XV

A 62 year old Caucasian female had thinning hair along her vertex. Thepatient began applying Formulation XX twice a day, approximately 2 mls aday, by spraying 1 ml a day along the vertex, twice a day. At Day 27,the patient switched to Formulation XVIII applied once a day, byspraying approximately 1 ml of formulation on her vertex each day. Thepatient sprayed Formulation XVIII for 30 days.

At Day 73, the patient's hair had significantly grown back along thevertex, with thicker and fuller hair with hair growth on the crown, butnot yet completely filled in.

Example XVI

A 59 year old Caucasian female with thinning hair long her vertex, beganapplying Formulation XX twice a day, approximately 2 ms a day, byspraying 1 ml a day onto the area of the scalp losing hair, twice a day.After 31 days, the patient switched to Formulation XVIII applied once aday, by spraying approximately 1 ml of formulation each day. The patientsprayed Formulation XVIII for 78 days. At Day 108, the patient's hairhad significantly regrown along the vertex.

Example XVII

A 64 year old Caucasian female with hair loss along her forehead andtemples began applying Formulation XX twice a day, approximately 2 ms aday, by spraying 1 ml a day onto the area of the scalp losing hair,twice a day. On Day 30, the patient switched to Formulation XVIIIapplied once a day, by spraying approximately 1 ml of formulation eachday. By Day 106, the patient experienced significant new hair growthalong her forehead and temples with hair that was darker and thickerthan the existing hair that was in those areas prior to treatment.

Example XVIII

A 26 year old Caucasian male with slight balding on his crown, beganapplying Formulation XX twice a day, approximately 2 ms a day, byspraying 1 ml a day onto the area of the scalp losing hair, twice a day.On Day 29, the patient switched to Formulation XVIII applied once a day,by spraying approximately 1 ml of formulation each day. On Day 99, thepatient experienced increased hair growth on his crown and the baldingarea was less visible.

Example XIX

A 44 year old Caucasian male had significant balding on his crowncorresponding roughly to a Norwood-Hamilton score of IV. The patientbegan applying Formulation XX twice a day, approximately 2 ms a day, byspraying 1 ml a day onto the area of the scalp losing hair, twice a day.On Day 29, the patient switched to Formulation XVIII applied once a day,by spraying approximately 1 ml of formulation each day. On Day 118, thepatient's hair had significantly grown back on the crown, with the hairdarker and thicker than the hair in the same area prior to treatment. ByDay 108, about half of the crown was grown in with terminal hair whereeither no hair or vellus hair previously existed.

Example XX

A 59 year old female patient with thinning along her vertexcorresponding to roughly an I-2 or I-3 on the Ludwig Scale, beganapplying Formulation XX twice a day, approximately 2 mls a day, byspraying 1 ml a day onto the area of the scalp losing hair, twice a day.On Day 30, the patient switched to Formulation XX twice a day,approximately 2 mls a day, by spraying 1 ml a day onto the area of thescalp losing hair, twice a day. On Day 99, the vertex was thicker andfuller with much of the vertex covered with new hair which was thickerthan the hair in the same area prior to treatment.

The invention claimed is:
 1. A composition for use in the treatment ofhair loss wherein the active agents consist of about 0.05%-0.5% w/vlatanoprost and 0.01%-0.1% w/v cyclosporine.
 2. The composition of claim1 further comprising oleyl alcohol or ethanol.
 3. The composition ofclaim 2 further comprising one selected from the group consisting ofpolyethylene glycol or propylene glycol.
 4. The composition of claim 3further comprising acetic acid and one selected from the groupconsisting of polysorbate 60 and polyoxyethylene lauryl alcohol.
 5. Thecomposition of claim 3 further comprising acetic acid one selected fromthe group consisting of polysorbate 60 and polyoxyethylene laurylalcohol.
 6. The composition of claim 2 further comprising ethanol and atleast one selected form the group consisting of propylene glycol andpolysorbate
 80. 7. The composition of claim 2 wherein ethanol is presentin a concentration of about 25%-30% w/v.
 8. The composition of claim 3wherein the composition further comprises oleyl alcohol.
 9. Thecomposition of claim 3 further comprising diethylene glycol monoethylether.
 10. The composition for use in hair loss wherein the activeagents consist of about 0.05-0.3% w/v latanoprost and 0.01%-0.1% w/vcyclosporine.
 11. The composition of claim 10 further comprisingethanol, propylene glycol, water and at least one selected from thegroup consisting of benzyl alcohol, oleic acid and polyoxyethylenelauryl alcohol.
 12. The composition of claim 10 wherein the compositioncomprises ethanol, propylene glycol, polysorbate, water and at least oneselected from the group consisting of oleyl alcohol, oleic acid andbenzyl alcohol.
 13. The composition of claim 12 wherein the compositioncomprises propylene glycol, ethanol and acetic acid and wherein aceticacid is present from about 0.1-0.5% w/v.
 14. The composition of claim 3wherein the composition comprises 50% w/v propylene glycol and 30% w/vethanol.
 15. The composition of claim 10 wherein the compositioncomprises at least two selected from the group consisting ethanol,propylene glycol, polyoxyethylene 80, and propanediol and at least oneselected from the group consisting of acetic acid, oleic acid and oleylalcohol.
 16. The composition according to claim 10 further comprisingabout 0.1% w/v latanoprost and about 0.1% w/v cyclosporine.
 17. Thecomposition according to claim 16 further comprising propylene glycol,ethanol, and diethylene glycol monoethyl ether.
 18. A compositionaccording to claim 17 wherein the composition comprises 50% w/vpropylene glycol, 25% w/v ethanol, 2-5% w/v diethylene glycol monoethylether and water.
 19. A composition according to claim 10 consisting of0.3% w/v latanoprost, 0.1% w/v cyclosporine, 3% w/v oleic acid, 50% w/vpropylene glycol, 30% w/v ethanol, water and 3% w/v diethylene glycolmonoethyl ether.
 20. A composition according to claim 10 consisting of0.1% w/v latanoprost, 0.1% w/v cyclosporine, 3% w/v oleic acid, 50% w/vpropylene glycol, 30% w/v ethanol, water and 2% w/v diethylene glycolmonoethyl ether.